記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: This study aims to investigate real-world data on the demographics, prescribing practices, and healthcare costs of juvenile idiopathic arthritis (JIA) with polyarthritis or oligoarthritis compared to rheumatoid arthritis (RA) patients in adolescents and young adults. METHODS: Data from the Japan Medical Data Center claims database for fiscal year (FY) 2016 to FY 2020 were analysed. JIA and RA were defined as having at least 2 months of disease-modifying antirheumatic drug (DMARD) prescriptions and corresponding International Classification of Diseases, 10th Revision codes for each FY. Therapeutic drug prescriptions and direct medical costs were evaluated. RESULTS: Among 5,064,539 eligible individuals aged 18-29 years, 202 were identified with JIA and 2758 with RA. The prescription rate of biologic and targeted synthetic DMARDs (tsDMARDs) for RA remained stable at ∼40% between FY 2016 and FY 2020. However, from FY 2018 onward, the rate was significantly higher for JIA, reaching ∼60% (P < .05). In FY 2020, biosimilar prescriptions accounted for 15% in RA but only 3% in JIA. Direct medical costs for JIA were 1.6 times higher than those for RA. CONCLUSIONS: Patients with JIA were more frequently prescribed tsDMARDs and less likely to receive biosimilars, contributing to higher healthcare costs compared to RA patients.

DOI： 10.1093/mr/roaf035

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: To identify unmet medical needs (UMNs) of medical practices and investigate the real-world prescribing practices of therapeutic medical treatments and test implementation for patients with juvenile idiopathic arthritis (JIA). METHODS: The possible UMNs were collected from eight paediatric and eight adult rheumatologists. To verify UMNs, the real-world prescribing practices of therapeutic medical treatments and test implementation for patients with JIA were described using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB). RESULTS: Fifty-eight possible UMNs collected from 16 experts and 35 UMNs were investigated using NDB. The highest priority UMNs was the expansion of indications for subcutaneous tocilizumab (TCZ sc) and subcutaneous abatacept- subcutaneous tocilizumab was administered to 12.8% systemic JIA and 5.5% JIA with polyarthritis or oligoarthritis. Comorbidities for systemic JIA and JIA with polyarthritis or oligoarthritis included hypertension (7.1%, 1.3%), osteoporosis (17%, 5.4%), depression (2.3%, 1.3%), diabetes (1.9% systemic JIA), and iritis and/or uveitis (6.5% JIA with polyarthritis or oligoarthritis). CONCLUSIONS: The highest priority UMNs for JIA was the expansion of indications for abatacept sc and especially subcutaneous tocilizumab. This study reveals the real-world prescribing practices of therapeutic medical treatments and test implementation for patients with JIA in Japan.

DOI： 10.1093/mr/roaf032

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1186/s13075-025-03597-6

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その他リンク： https://link.springer.com/article/10.1186/s13075-025-03597-6/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To investigate differences in autoantibodies, clinical features, and long-term outcomes between juvenile- and adult-onset systemic sclerosis (SSc). METHODS: Autoantibodies and survival rates over a maximum of 20 years were retrospectively analysed in 504 Japanese patients with SSc (juvenile-onset SSc, n = 17; adult-onset SSc, n = 487) using data from Kyoto University Registry. RESULTS: : The autoantibodies observed were anti-topoisomerase-I (71% vs. 26%), anti-centromere (24% vs. 54%), and anti-RNA-polymerase-III (0% vs. 12%). A diffuse type and multiorgan involvement were observed in patients with anti-topoisomerase-I in both juvenile- and adult-onset SSc. In patients with anti-centromere, a diffuse type (juvenile-onset SSc vs. adult-onset SSc, 75% vs. 28%) and pulmonary fibrosis (50% vs. 17%) were more frequently observed in juvenile-onset SSc than in adult-onset SSc. Cox proportional hazard analyses showed that older onset (hazard ratio: 1.06, 95% confidence interval: 1.03-1.09) was associated with death, while autoantibodies were not significantly associated with death. Cumulative survival rates for 20 years were similar between juvenile- and adult-onset SSc when classified based on the presence of anti-centromere (100% vs. 89%, P = .20) and anti-topoisomerase-I (90% vs. 90%, P = .70). CONCLUSIONS: : Juvenile-onset SSc had more frequent diffuse-type and anti-topoisomerase-I. An older onset was slightly associated with mortality, whereas autoantibodies were not associated with mortality.

DOI： 10.1093/mr/roaf005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Patients with autoimmune and autoinflammatory diseases experience difficult physical, mental, and social situations and have various unmet medical needs (UMNs). To provide appropriate solutions for these patients, an accurate understanding of their UMNs is necessary. Patient-reported outcomes (PROs) reflect the problems of patients and are highly likely to be useful in understanding patient needs. This article reviews established PRO measures from the perspective of determining those appropriate for identifying the UMNs of patients with autoimmune and autoinflammatory diseases. To consider appropriate PRO measures, discussions were held by experts at the Ministry of Health, Labor and Welfare group meetings. The possibility of developing a method to collect PRO data electronically using information and communication technology was also considered. The experts proposed 28 measures, both disease-specific and non-disease-specific, as candidates. It was confirmed that linguistic validation was important and that measures obtained from adults and children could not be considered together. A migration from paper to digital PRO measures was not conducted due to the need for ensuring accuracy and the shortage of technical and financial support. Appropriate non-disease-specific PRO measures were considered to be the KINDL® and EQ-5D-Y for children and the SF-36v2® and EQ-5D™ for adults.

DOI： 10.1093/mr/roaf036

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.alit.2024.10.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Individuals diagnosed with Castleman disease (CD) and TAFRO syndrome (characterized by thrombocytopenia, anasarca, fever, bone marrow fibrosis, and organomegaly) displays a wide range of clinical symptoms, including varying patterns of lymph node enlargement, systemic inflammation, and impaired organ function. Some patients may present with both CD and TAFRO syndrome concurrently. A retrospective study conducted across multiple centers in Japan examined 321 cases to determine if the quantity and position of swollen lymph nodes could forecast the clinical progression and intensity of these conditions. Interestingly, the study revealed that patients with TAFRO syndrome exhibited lymphadenopathy across all ranges of lymph node region counts. Moreover, no specific clinical patterns were associated with the number of affected lymph node regions in CD patients, regardless of whether they also had TAFRO syndrome. These results enhance our understanding of the clinical variability in CD and TAFRO syndrome, suggesting that a comprehensive clinical evaluation, rather than relying solely on lymph node count, is crucial for effectively managing these conditions. Additional studies are required to establish reliable diagnostic markers and to predict disease severity at the time of diagnosis, ultimately improving patient outcomes.

DOI： 10.1002/ajh.27612

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Abstract

Sarcoidosis is a multisystem disorder characterized by non-caseating granulomas, often involving the lungs and lymph nodes, but can affect nearly any organ. Renal involvement in sarcoidosis typically presents as hypercalcemia or interstitial granulomatous nephritis. Renal vasculitis, however, is an exceedingly rare manifestation. We present a case of a 74-year-old Japanese male who was diagnosed with esophageal cancer and underwent chemoradiotherapy. He presented with hypercalcemia and renal dysfunction, and laboratory tests revealed elevated serum creatinine and hypercalcemia. Fluorodeoxyglucose-positron emission tomography/computed tomography showed intense uptake in the gluteal and adductor muscles, with no recurrence of esophageal cancer. A muscle biopsy confirmed non-necrotizing granulomas. Despite correction of hypercalcemia, proteinuria and renal dysfunction persisted, prompting a renal biopsy. The biopsy revealed pauci-immune vasculitis, with fibrin deposition and destruction of the vascular elastic lamina, without granulomas. The patient was treated with corticosteroids, which led to significant improvement in renal function and proteinuria. This case highlights the rare coexistence of sarcoidosis and renal vasculitis. Thus, even in the presence of mild urinary abnormalities, renal biopsy should be considered in the diagnostic approach to sarcoidosis patients with renal dysfunction.

DOI： 10.1093/mrcr/rxaf018

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Polyunsaturated fatty acids (PUFAs) are healthy fats that contain a double carbon bond. They are made up of omega (ω)-3 and ω-6 PUFAs, where ω-3 PUFAs exhibit beneficial effects, such as the suppression of cardiovascular events and the improvement of abnormal lipid metabolism. Though, their effects on rheumatoid arthritis (RA) are unclear. Epoxy fatty acids (EpFAs), which are intermediate metabolites of ω-6 and ω-3 PUFAs, are formed through the action of cytochrome P and possess anti-inflammatory properties. However, they are quickly converted into their inactive forms by soluble epoxide hydrolase (sEH). METHODS: The protective effects of ω-3 and ω-6 PUFAs on arthritic symptoms with or without sEH inhibitors (sEHi) were investigated in a collagen-induced arthritis mouse model. RESULTS: The group treated with a combination of ω-3 PUFAs and sEHi showed a marked inhibition of arthritis compared to the other groups. Analysis of the faecal flora before the onset of arthritis showed an inverse correlation between the arthritis score and the relative abundance of Lactococcus, suggesting that changes in the intestinal flora in the preclinical stage may influence the onset of arthritis. CONCLUSIONS: This study highlights the potential of ω-3 PUFAs combined with sEHi as novel protective effect for RA.

DOI： 10.1093/mr/roaf019

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: To analyse the association of anti-dsDNA Ab with patient-reported outcomes (PROs) in patients with SLE under maintenance treatment, as it has not been clearly understood whether PROs are able to be reflected by anti-dsDNA, which are associated with SLE activities (SLE Disease Activity Index 2000, SLEDAI-2K). METHODS: The SLE symptom checklist (SSC), LupusPRO, Medical Outcomes Study Short Form-36 (SF-36), and patient and physician visual analogue scale (Pt/Ph-VAS) at a time point were evaluated for correlation with anti-dsDNA using the Kyoto Lupus Cohort Registry (n = 310) from 2019 to 2020. Further, associations between changes in anti-dsDNA with those in Pt/Ph-VAS and SSC at two time points of short-term (3 months) or long-term (2 years) time points. RESULTS: Cross-sectionally, anti-dsDNA slightly correlated with Ph-VAS (ρ = 0.18, p = 0.003) and SLEDAI-2K (ρ = 0.14, p = 0.03), while anti-dsDNA was not correlated with SSC, SF-36, and LupusPRO, or Pt-VAS. In short-term and long-term, anti-dsDNA demonstrated no significant correlation with alterations in SSC, Pt-VAS, or Ph-VAS. Further, they did not show associations when SLE activities (SLEDAI-2K) were worsened. CONCLUSION: PROs at a time point and changes were difficult to be captured by anti-dsDNA. It is desirable to explore objective laboratory measures to evaluate PROs.

DOI： 10.24546/0100492949

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Objective

To evaluate the ability to discriminate giant cell arteritis (GCA) from Takayasu arteritis (TAK) according to the modified 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) GCA classification criteria.

Methods

Patients enrolled in the Japanese nationwide retrospective registry were evaluated using the criteria with partial modification; wall thickening of descending thoracic-abdominal aorta were mainly diagnosed by contrast-enhanced computed tomography (CT) or magnetic resonance imaging instead of evaluating with positron emission tomography (PET)-CT. The discriminability of the criteria was evaluated using C-statistic (&gt; 0.7: good ability).

Results

Newly diagnosed patients with GCA (n = 139) and TAK (n = 129) were assessed, and 23.3% of TAK were aged 50 years or older at onset. The sensitivity of the modified 2022 ACR/EULAR GCA classification criteria with a score ≥ 6 was 82.0%, 68.5%, and 32.1% in all GCA, GCA with large-vessel involvement, and GCA without cranial arteritis, respectively. The specificity of the modified criteria was 96.1% for the 129 TAK as controls. Five patients with late-onset TAK met the modified criteria, and four had cranial signs and symptoms, two had bilateral axillary artery involvement, and four had descending thoracic-abdominal aorta involvement. The discriminability of the criteria was good (C-statistic: 0.986, 95% confidence interval [CI]: 0.976–0.996) and remained good after excluding age (C-statistic: 0.927, 95% CI: 0.894–0.961). The discriminability of a set of large-vessel lesions (bilateral axillary artery and descending thoracic-abdominal aorta) and inflammatory markers was markedly decreased with poor C-statistic value (C-statistic: 0.598, 95% CI: 0.530–0.667). Discriminability was improved after adding polymyalgia rheumatica (PMR) (C-statistic: 0.757, 95% CI: 0.700–0.813) or age (C-statistic: 0.913, 95%CI: 0.874–0.951) to the set of large-vessel lesions. In GCA patients with a score ≤ 5, 52% had bilateral subclavian and/or axillary artery involvement.

Conclusion

The modified 2022 ACR/EULAR GCA classification criteria well performed in classifying GCA and TAK without PET-CT in routine clinical practice. A set of items included in the modified GCA classification criteria had good discriminative ability for GCA and TAK, even when age was excluded. However, age restriction or PMR was required to distinguish GCA without cranial lesions from TAK.

DOI： 10.1186/s13075-025-03486-y

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その他リンク： https://link.springer.com/article/10.1186/s13075-025-03486-y/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Takayasu arteritis (TAK) is a rare, chronic large vessel vasculitis with unmet treatment needs. This phase 3 study aimed to evaluate efficacy, safety, pharmacokinetics and immunogenicity of ustekinumab (UST) in Japanese patients with TAK. METHODS: Patients with TAK who had relapsed ≤12 weeks prior to study intervention administration and achieved remission thereafter with standard-of-care including corticosteroid intensification were randomized 1:1 to receive UST or matching placebo with protocol-defined oral glucocorticoid taper regimen. The double-blind (DB) phase was up to the patient's relapse/total of 35 relapse events, followed by the open-label extension (OLE) phase. Primary endpoint was the time to relapse of TAK per protocol-defined criteria through the end of the DB phase. RESULTS: The study was terminated early due to patient recruitment challenge. Of 14 patients randomized, 8 relapsed during the DB phase (UST: 4/6; placebo: 4/8). The median time to relapse (weeks) was 11.14 (95% CI: 4.14, not estimated [NE]) for UST and 12.64 (95% confidence interval [CI]: 12.14, NE) for placebo (hazard ratio [HR] = 1.86 [95% CI: 0.41, 8.47]). In the DB phase, one patient in each group reported serious adverse event (SAE; UST: vascular pseudoaneurysm and brachiocephalic artery stenosis; placebo: cholecystitis); none were related to study intervention. Through the OLE phase, 1/4 (25.0%) patients in the UST-UST group (vascular graft infection considered related to study intervention) and none in the placebo-UST had SAEs. There were no serious infections/deaths throughout the study. CONCLUSION: The efficacy of UST in patients with TAK cannot be adequately assessed as the pre-determined sample size was not reached, and the study was prematurely terminated. No new safety signal of UST was identified. TRIAL REGISTRATION: Clinicaltrials.gov, https://clinicaltrials.gov, NCT04882072; jrct.niph.go.jp, https://jrct.niph.go.jp, jRCT2061210007; Clinical Registry, CR108981.

DOI： 10.1093/rap/rkaf013

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The factors contributing to the treatment efficacy of belimumab in patients with systemic lupus erythematosus (SLE) in the maintenance phase are unknown. Here, we collected blood samples from patients with SLE (n=44) treated with belimumab before and three and six months after treatment. RNA-Seq of whole blood was performed, and gene expression was quantified. Immune cell type enrichment analysis estimated immune cell subtype proportions and gene expression in each subtype. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) < 4 at six months was set as the primary efficacy criterion. Non-responders exhibited upregulated B cell proliferation signals before treatment, associated with an increased number of memory B cells. A higher proportion of memory B cells before treatment predicted poor response (p=5.1×10-4). This was also associated with changes in disease activity and glucocorticoid dose at six months compared with baseline. Belimumab did not affect memory B cell proportion during the treatment time course, in contrast to naïve B cells. Higher memory B cell proportion was associated with higher type-I interferon (IFN) scores and lower white blood cell and complement C4 levels. Transcriptomic analysis of memory B cells in non-responders revealed significant upregulation of immunoglobulin genes (Ig). Memory B cells and high Ig expression in them were identified as a treatment-resistant factor of belimumab in SLE patients. Lower C4 and white blood cell counts may serve as clinical markers of higher memory B cells.

DOI： 10.3389/fimmu.2025.1506298

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Informa UK Limited  

We started a registry for cases of immunoglobulin (Ig)G4-related disease (IgG4-RD) in December 2019 to clarify the clinical profile of IgG4-RD. In this study, clinical information from 854 cases registered by February 16, 2024 was analyzed from multiple perspectives. Diagnosis of IgG4-RD was made in 808 cases, comprising 638 definite, 38 probable, and 132 possible. The mean ± SD age at time of enrollment of the 808 cases was 67.9 ± 11.3 years, with 68.8% being male. The pancreas was the most frequently affected organ (49.8%), followed by the submandibular glands (46.2%) and lacrimal glands (30.6%). This study reconfirmed the pancreas and head-and-neck region as major affected areas in IgG4-RD. Clinically, submandibular adenitis and autoimmune pancreatitis often occur together in the same patient, but no association between the two organs was observed in our analysis. Regarding diagnosis, the comprehensive diagnostic criteria were most commonly used (63.6%). Storiform fibrosis and phlebitis obliterans were detected at different frequencies in different organs. In summary, this registry study identified clinical, imaging, hematologic, and pathologic findings in 808 Japanese patients with IgG4-RD. The frequency of affected organs and their characteristic pathological findings will be particularly useful for future practice.

DOI： 10.1080/25785826.2024.2430812

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Autoantibodies are detected in idiopathic interstitial pneumonias (IIPs) without a clear connective tissue disease diagnosis, and their clinical significance is unclear. This study aimed to identify a novel autoantibody in IIPs. We screened 295 IIP patients using a 35S-methionine labeled protein immunoprecipitation assay. Candidate autoantigens were identified via protein array and confirmed by immunoprecipitation. Six sera from 295 IIP patients immunoprecipitated common tetrameric proteins (100 kDa). The protein array identified interferon gamma-inducible protein 16 (IFI16) as the candidate autoantigen. Patients with anti-IFI16 antibodies received immunosuppressants less frequently. Five-year survival rates were 50 %, 69 %, and 63 % (P = 0.60), and acute exacerbation-free rates were 50 %, 96 %, and 84 % (P = 0.15) for patients with anti-IFI16, anti-aminoacyl tRNA antibodies, and others. Anti-IFI16 is a novel autoantibody in IIPs. Patients with this antibody often receive less immunosuppressive therapy and could have a poor prognosis. Further research is needed to refine patient stratification and management.

DOI： 10.1016/j.clim.2024.110372

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: For the diagnosis of IgG4-related dacryoadenitis and sialadenitis, either revised comprehensive diagnostic criteria or organ-specific diagnostic criteria for IgG4-related dacryoadenitis and sialadenitis in 2008 were applied; however, the collected knowledge for IgG4-related dacryoadenitis and sialadenitis required us to revise the criteria for IgG4-related dacryoadenitis and sialadenitis. METHODS: The board member of Japanese Study Group for IgG4-related Dacryoadenitis and Sialadenitis revised the diagnostic criteria for IgG4-related dacryoadenitis and sialadenitis. We collected the clinical questions to be revised and performed a review of the literature. When the data were insufficient, additional data collection was performed. After the revision, public comments were collected. RESULTS: The three major points were revised. 1. Asymmetric or under two pairs of dacryoadenitis and sialoadenitis were included as IgG4-related dacryoadenitis and sialadenitis. 2. The thresholds of IgG4-positive cell infiltration were adjusted to an IgG4+/IgG+ ratio >0.4 and IgG4+ cells >10 per high power field. 3. The labial salivary gland biopsy was allowed to diagnose IgG4-related dacryoadenitis and sialadenitis. CONCLUSIONS: The revised diagnostic criteria for IgG4-related dacryoadenitis and sialadenitis solved several issues with the previous criteria. It will improve the early diagnosis of IgG4-related dacryoadenitis and sialadenitis, especially in situations without enough resources for a biopsy.

DOI： 10.1093/mr/roae096

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To investigate differences in autoantibodies, clinical features, and long-term outcomes between juvenile-idiopathic inflammatory myopathy (IIM) and adult-IIM METHODS: Autoantibodies, clinical characteristics, and drug-free conditions for a maximum of 20 years were retrospectively analyzed in 320 Japanese IIM patients (juvenile-IIM, n = 34; adult-IIM, n = 286) using the Kyoto University Registry. RESULTS: Autoantibodies observed in juvenile-IIM were anti-TIF1-γ (15 %), anti-MDA-5 (15 %), anti-ARS (9 %), and anti-NXP-2 (6 %). Those observed in adult-IIM were anti-ARS (32 %), anti-MDA-5 (23 %), anti-TIF1-γ (8 %), anti-SRP (8 %), anti-Mi-2 (2 %), and anti-NXP-2 (1 %). The cumulative drug-free condition rate was higher in juvenile-IIM than in adult-IIM up to 20 years (juvenile-IIM vs. adult-IIM, 34 % vs. 18 %, p = 0.0016). Anti-TIF1-γ was associated with lesser muscle symptoms (60 % vs. 90 %), malignancy (0 % vs. 57 %), and glucocorticoid use (40 % vs. 86 %) in juvenile-IIM compared to adult-IIM, while juvenile-IIM more achieved drug-free conditions (60 % vs. 25 %). Both juvenile-IIM and adult-IIM with anti-MDA-5 demonstrated a high frequency of amyopathic dermatomyositis, interstitial lung disease (ILD), and multi-immunosuppressive therapy, with high drug-free conditions (50 % vs. 49 %). Both juvenile-IIM and adult-IIM with anti-ARS showed frequent skin rashes, muscle symptoms, and ILD, frequent need for multi-immunosuppressive therapy, and low drug-free condition rates (0 % vs. 3 %). Both juvenile-IIM and adult-IIM with anti-NXP-2 showed frequent skin rashes and muscle symptoms, low ILD frequency, and frequent use of methotrexate and glucocorticoids, which did not achieve drug-free conditions (0 % vs. 0 %). CONCLUSIONS: Drug-free condition was achieved more frequently in juvenile-IIM patients than adult-IIM patients. Specific autoantibodies were associated with different clinical characteristics and outcomes between juvenile-IIM and adult-IIM.

DOI： 10.1016/j.semarthrit.2024.152530

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: In 2018, diagnostic criteria were introduced for IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis (PA/RPF). This study assessed the existing criteria and formulated an improved version. METHODS AND RESULTS: Between August 2022 and January 2023, we retrospectively analyzed 110 Japanese patients diagnosed with IgG4-related disease (IgG4-RD) involving cardiovascular and/or retroperitoneal manifestations, along with 73 non-IgG4-RD patients ("mimickers") identified by experts. Patients were stratified into derivation (n=88) and validation (n=95) groups. Classification as IgG4-RD or non-IgG4-RD was based on the 2018 diagnostic criteria and various revised versions. Sensitivity and specificity were calculated using experts' diagnosis as the gold standard for the diagnosis of true IgG4-RD and mimickers. In the derivation group, the 2018 criteria showed 58.5% sensitivity and 100% specificity. The revised version, incorporating "radiologic findings of pericarditis", "eosinophilic infiltration or lymphoid follicles", and "probable diagnosis of extra-PA/-RPF lesions", improved sensitivity to 69.8% while maintaining 100% specificity. In the validation group, the original and revised criteria had sensitivities of 68.4% and 77.2%, respectively, and specificities of 97.4% and 94.7%, respectively. CONCLUSIONS: Proposed 2023 revised IgG4-related cardiovascular/retroperitoneal disease criteria show significantly enhanced sensitivity while preserving high specificity, achieved through the inclusion of new items in radiologic, pathological, and extra-cardiovascular/retroperitoneal organ categories.

DOI： 10.1253/circj.CJ-24-0026

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掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE Publications  

Objectives

There are often discrepancies in the evaluation of disease activity between patients and physicians in systemic lupus erythematosus (SLE). In this study, we examined the factors that affect those evaluations.

Methods

Physician visual analogue scale (Ph-VAS), patient VAS (Pt-VAS), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2k), glucocorticoid (GC) usage and dose, age, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, and three patient-reported outcomes (SLE symptom checklist [SSC], short-form 36 questionnaire [SF-36], and LupusPRO) were obtained from a study performed in 2019 using 225 SLE outpatients of the Kyoto Lupus Cohort at Kyoto University Hospital. Correlations among Ph-VAS, Pt-VAS, or dif (Pt-VAS-Ph-VAS) (Pt-VAS minus Ph-VAS) and other factors were examined.

Results

We found a significant discrepancy between Pt-VAS (median 38.0 mm) and Ph-VAS (median 18.7 mm) scores ( p &lt; 0.001). SSC score showed a significant correlation with Pt-VAS and dif (Pt-VAS-Ph-VAS) ( p &lt; 0.001). Among SSC items, fatigue showed the most significant correlation with dif (Pt-VAS-Ph-VAS). We also showed that higher dif (Pt-VAS-Ph-VAS) was associated with lower quality of life (QOL) evaluated by SF-36 and LupusPRO.

Conclusions

Pt-VAS scores tended to be higher than Ph-VAS scores, and the discrepancy was influenced mainly by fatigue. Higher dif (Pt-VAS-Ph-VAS) was associated with lower patient QOL.

DOI： 10.1177/09612033241281909

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その他リンク： https://journals.sagepub.com/doi/full-xml/10.1177/09612033241281909

掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Circulation Society  

DOI： 10.1253/circj.cj-24-0178

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Bacterial translocation across the gut barrier has been implicated in the pathogenesis of systemic lupus erythematosus (SLE), though underlying mechanisms remain unclear. This study aimed to investigate the role of translocated bacteria in the context of molecular mimicry by utilizing lupus model mice and blood samples from untreated SLE patients. METHODS: Bacterial translocation was evaluated using nonselective cultured mesenteric lymph nodes (MLNs) from B6SKG mice, a lupus model characterized by impaired TCR signalling and gut dysbiosis. The relationships of detected pathobionts with autoantibody production were examined using in vivo experiments, enzyme-linked immunosorbent assay, immunoblotting, and epitope mapping. RESULTS: Culture-based bacterial profiling in MLNs demonstrated that Lactobacillus murinus was enriched in B6SKG mice with elevated anti-dsDNA IgG levels. Subcutaneous injection of heat-killed L. murinus induced anti-dsDNA IgG production without altering T- or B cell subset composition. Immunoblotting and mass spectrometry analysis identified a peptide ATP-binding cassette (ABC) transporter as a molecular mimicry antigen, with its cross-reactivity in lupus mice confirmed by serological assays and in vivo immunization. The L. murinus ABC transporter exhibited surface epitopes that were cross-reactive with sera from lupus mice and patients. The ABC transporter from R. gnavus, known for its pathogenic role in lupus patients, had a similar epitope sequence to that of the L. murinus ABC transporter and reacted with lupus sera. CONCLUSION: ABC transporters from gut bacteria can serve as cross-reactive antigens that may promote anti-dsDNA antibody production in genetically susceptible mice. These findings underscore the role of commensal-derived molecular mimicry and bacterial translocation in lupus pathogenesis.

DOI： 10.1093/rheumatology/keae476

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Anti-aminoacyl-tRNA synthetase (ARS) antibodies are myositis-specific antibodies associated with anti-synthetase syndrome (ASSD). Some patients are positive for anti-ARS antibodies on enzyme-linked immunosorbent assay (ELISA) but negative on RNA-immunoprecipitation (RNA-IP) (the gold standard method). Whether these patients should be considered truly positive for anti-ARS antibodies remains unclear. Therefore, we investigated the clinical characteristics of these patients and verified the authenticity of their anti-ARS positivity. Patients who were positive for anti-ARS antibodies on ELISA were divided into the non-discrepant (positive on RNA-IP, n = 52) and discrepant (negative on RNA-IP, n = 8) groups. Patient clinical characteristics were compared between the groups. For each positive individual, the authenticity of anti-ARS antibody positivity on ELISA was cross-examined using protein-IP and western blotting. All patients in the discrepant group had lung involvement, including five (63%) with interstitial lung disease. The overall survival time was significantly lower in the discrepant group than in the non-discrepant group (p < 0.05). Validation tests confirmed the presence of anti-ARS antibodies in the sera of the discrepant group but indicated different reactivity from typical anti-ARS antibodies. In conclusion, some anti-ARS antibodies are detected by ELISA but not RNA-IP. Such anti-ARS antibody discrepancies need further elucidation to attain validation of the diagnostic process in ASSD.

DOI： 10.1080/25785826.2024.2328918

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: This study aimed to understand the status quo of medical treatments of the primary disease and pregnancy outcomes in patients with Takayasu arteritis (TAK) and children's birth outcomes. METHODS: This study retrospectively enrolled patients with TAK who conceived after the disease onset and were managed at medical facilities participating in the Japan Research Committee of the Ministry of Health, Labor, and Welfare for Intractable Vasculitis. RESULTS: This study enrolled 51 cases and 68 pregnancies 2019-2021. Of these, 48 cases and 65 pregnancies (95.6%) resulted in delivery and live-born babies. The median age of diagnosis and delivery was 22 and 31, respectively. Preconception therapy included prednisolone (PSL) in 51 (78.5%, median 7.5 mg/day), immunosuppressants in 18 (27.7%), and biologics in 12 (18.5%) pregnancies. Six cases underwent surgical treatment before pregnancy. Medications during pregnancy included PSL in 48 (73.8%, median: 9 mg/day), immunosuppressants in 13 (20.0%), and biologics in 9 (13.8%) pregnancies. Enlargement of an aneurysm was reported in one pregnancy, which might be associated with increased circulating plasma volume. TAK relapsed in 4 (6.2%) and 8 (12.3%) pregnancies during pregnancy and after delivery, respectively. Additionally, 13/62 (20.9%) preterm infants and 17/59 (28.8%) low birth weight infants were observed, and none had serious postnatal abnormalities. Of the 51 confirmed infants, 42 (82.4%) were exclusively breastfed or mixed with formula. CONCLUSION: Most pregnancies in TAK were manageable with PSL at ≤10 mg/day. Relapse during pregnancy and postpartum occurred in <20% of pregnancies.

DOI： 10.1093/mr/roae068

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Vesiculobullous dermatomyositis (VD) is a rare manifestation of dermatomyositis (DM) and has been suggested to be associated with malignancy. Although the myositis-specific autoantibodies are associated with distinct clinical presentations of DM, those associated with VD remain unclear. Here, we present the case of a 54-year-old man with VD who tested positive for anti-nuclear matrix protein 2 (NXP-2) antibody, one of the DM-specific autoantibodies. Serological and histopathological findings did not support autoimmune blistering disease. Physical and histological findings suggested that the severe edema in combination with the interface dermatitis of DM contributed to blister formation. Although a systemic examination was performed, no evidence of malignancy was found. Following initiation of immunosuppressive therapy, the patient showed significant improvement in both skin lesions and myositis. This case represents the first report of anti-NXP-2-positive VD without malignancy or autoimmune blistering disease. Subcutaneous edema, a characteristic feature of anti-NXP-2-positive DM, could be related to the formation of VD.

DOI： 10.1093/mrcr/rxae037

PubMed

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1346-8138.17067

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Infections are a critical concern for patients with microscopic polyangiitis (MPA). This study aimed to identify the risk factors associated with serious infections (SIs) and infection-related mortality in patients with MPA, as well as the effect of glucocorticoid (GC) dose tapering on these outcomes. METHODS: This multicentre, retrospective, and observational study utilised data from a cohort of patients with MPA in Japan [Registry of Vasculitis Patients to Establish REAL World Evidence (REVEAL) cohort]. Patients were categorised based on the occurrence of SIs or infection-related deaths, and various characteristics were compared among the groups. RESULTS: Among 182 patients, 66 (36.2%) experienced 129 SIs and 27 (14.8%) developed infection-related deaths. Advanced age, elevated C-reactive protein (CRP) levels, and higher ratio of the GC dose at 3 months to the initial dose were identified as independent risk factors for SIs. Older age was also associated with infection-related deaths. Furthermore, the cumulative incidence of infection-related deaths was significantly higher in patients with a higher ratio of the GC dose at 24 months to the initial dose. CONCLUSION: Older age, elevated CRP levels, and slower GC dose tapering predispose patients to SIs and infection-related deaths. Strategies, such as rapid GC dose tapering, are anticipated to mitigate the risk of infections.

DOI： 10.1093/mr/roae024

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Avacopan, an orally administered C5a receptor antagonist, is effective in microscopic polyangiitis via the inhibition of neutrophil priming induced by C5a. However, the exact effect of avacopan on the production of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) is yet to be clearly established. This report presents a microscopic polyangiitis patient without major organ damage where high levels of MPO-ANCA persisted with high-dose steroid therapy and azathioprine, but the addition of avacopan led to a reduction in MPO-ANCA titres. The present case implies that avacopan-mediated inhibition of C5a may lead to a reduction in MPO-ANCA levels, thereby potentially ameliorating the pathophysiology of ANCA-associated vasculitis. Nevertheless, the impact of avacopan on MPO-ANCA production cannot be asserted solely based on this report; therefore, further examination is necessary through subgroup analysis using data from larger-scale studies.

DOI： 10.1093/mrcr/rxae016

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Several animal disease models have been used to understand the mechanisms of systemic lupus erythematosus (SLE); however, the translation of findings from animals to humans has not been sufficiently examined in drug development. To confirm the validity of New Zealand black x New Zealand white (NZB/W) F1 mice as an SLE model, we extensively characterized SLE patients and NZB/W F1 mice by omics analysis. METHODS: Peripheral blood from patients and mice and spleen and lymph node tissue from mice were analysed using cell subset analysis, cytokine panel assays, and transcriptome analysis. RESULTS: CD4+ effector memory T cells, plasmablasts, and plasma cells were increased in both SLE patients and NZB/W F1 mice. Levels of tumor necrosis factor-α, interferon gamma induced protein-10, and B cell activating factor in plasma were significantly higher in SLE patients and NZB/W F1 mice than in their corresponding controls. Transcriptome analysis revealed an upregulation of genes involved in the interferon signalling pathway and T-cell exhaustion signalling pathway in both SLE patients and the mouse model. In contrast, death receptor signalling genes showed changes in the opposite direction between patients and mice. CONCLUSION: NZB/W F1 mice are a generally suitable model of SLE for analysing the pathophysiology and treatment response of T/B cells and monocytes/macrophages and their secreted cytokines.

DOI： 10.1093/mr/road024

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

TAFRO syndrome is an acute systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly. There have been increasing reports that TAFRO is a disease distinct from idiopathic multicentric Castleman disease and that TAFRO patients may be positive for anti-SSA antibodies. To assess anti-SSA antibody positivity and the clinical characteristics of the two diseases, we retrospectively compared 7 TAFRO and 10 iMCD patients in our hospital. The mean age of onset of TAFRO and iMCD was 48.0 (interquartile range [IQR], 41-53) and 45.0 (IQR, 35-53) years, respectively. The TAFRO and iMCD groups had 6 (86%) and 4 (40%) male patients, respectively, and the following pretreatment laboratory values: platelet count, 3.8 (IQR, 2.2-6.4) and 35.5 (IQR, 22.2-42.8) × 104/μL, respectively; C-reactive protein, 10.2 (IQR, 6.8-21.4) and 9.5 (IQR, 6.2-13.6) mg/dL, respectively; IgG, 1431 (IQR, 1112-1815) and 4725 (IQR, 3755-5121) mg/dL, respectively. RNA immunoprecipitation (5 cases for anti-SSA) or protein array (5 cases for anti-SSA/Ro60) detected anti-SSA antibodies in six (86%) TAFRO patients but not in iMCD patients; it did not detect anti-SSB antibodies in any of the patients. None of the patients were diagnosed with Sjögren syndrome. All iMCD patients treated with tocilizumab (TCZ) responded well. Meanwhile, two of six TAFRO patients treated with TCZ showed inadequate responses; thus, both patients were switched to rituximab, following which they achieved remission. TAFRO and iMCD have different clinical features. TAFRO may be categorized as a severe phenotype of the anti-SSA antibody syndrome.

DOI： 10.1038/s41598-024-53413-5

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記述言語：日本語   出版者・発行元：医歯薬出版(株)  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J00060&link_issn=&doc_id=20240206010014&doc_link_id=issn%3D0039-2359%26volume%3D288%26issue%3D5%26spage%3D425&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0039-2359%26volume%3D288%26issue%3D5%26spage%3D425&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s13691-023-00646-2

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その他リンク： https://link.springer.com/article/10.1007/s13691-023-00646-2/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: It has been well documented that Takayasu arteritis (TAK) and ulcerative colitis (UC) coexist in the same patients. HLA-B*52 characterizes the co-occurrence, which is one of the common genetic features between these two diseases, indicating shared underlying pathologic mechanisms. Anti-integrin αvβ6 antibody (Ab) is present in sera of UC patients in a highly specific manner. We investigated if there were any associations between anti-integrin αvβ6 Ab and TAK, considering the risk HLA alleles. METHODS: A total of 227 Japanese TAK patients were recruited in the current study and their serum samples were subjected to measurement of anti-integrin αvβ6 Ab by ELISA. The clinical information, including the co-occurrence of UC, was collected. The HLA allele carrier status was determined by Luminex or genotype imputation. RESULTS: The information about the presence of UC was available for 165 patients, among which eight (4.84%) patients had UC. Anti-integrin αvβ6 antibody was identified in 7 out of 8 TAK subjects with UC (87.5%) while only 5 out of 157 (3.18%) TAK subjects without UC had the antibody (OR 121, p=7.46×10-8). A total of 99 out of 218 (45.4%) patients were HLA-B*52 carriers. There was no significant association between the presence of anti-integrin αvβ6 Ab and HLA-B*52 carrier status in those without UC (OR 2.01, 95% CI 0.33-12.4, p = 0.189). CONCLUSIONS: The prevalence of anti-integrin αvβ6 Ab was high in TAK patients with UC, but not in the absence of concomitant UC. The effect of HLA-B*52 on anti-integrin αvβ6 Ab production would be minimal.

DOI： 10.3389/fimmu.2024.1387516

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ig (immunoglobulin) G4-related disease (Ig4-RD) affects several organs, including salivary glands, lacrimal glands, pancreas, biliary ducts, and retroperitoneum. A 72-year-old woman was examined for hypereosinophilia, high levels of IgG4, polyneuropathy, liver dysfunction, enlargement of lymph nodes and lacrimal glands, and beaded dilation of the bile ducts. We diagnosed Ig4-RD based on biopsies of the lymph nodes, liver, and submandibular gland. The symptoms of the patient improved after glucocorticoid treatment. This was a novel and atypical case of Ig4-RD that was difficult to differentiate from other diseases, including eosinophilic granulomatosis with polyangiitis, idiopathic hypereosinophilic syndrome, and polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes syndrome. This case report highlights the importance of biopsies in differentiating Ig4-RD.

DOI： 10.1093/mrcr/rxad053

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Takayasu arteritis, affecting primarily young women, damages large arteries and organs. We examined the impact of disease duration and sex on organ damage and quality of life using Japan's Intractable Disease Registry.Methods and Results: After refining data, 2,013 of 2,795 patients were included in the study. Longer disease duration was related to a lower prevalence of disease activity symptoms, a higher prevalence of organ damage, and a higher proportion of patients requiring nursing care. Compared with men, women tended to have an earlier onset age, exhibiting longer disease duration. A higher proportion of women had aortic regurgitation and required nursing care. The proportion of female patients in employment was lower than that of the general female population, whereas no difference was observed between male patients and the general male population. Logistic regression analysis revealed that age at surveillance, brain ischemia, visual impairment/loss, and ischemic heart disease were significant factors associated with high nursing care needs (Level ≥2, with daily activity limitations). CONCLUSIONS: Early diagnosis and effective treatment, particularly to prevent brain ischemia, visual impairment, and ischemic heart disease, may improve the quality of life of patients with Takayasu arteritis, especially women.

DOI： 10.1253/circj.CJ-23-0656

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Antimelanoma differentiation-associated gene 5 (anti-MDA5)-positive dermatomyositis with interstitial lung disease (DM-ILD) progresses rapidly and has a poor prognosis. Previously, we reported the efficacy of a combination therapy comprising high-dose glucocorticoids (GCs), calcineurin inhibitors (CNIs), and intravenous cyclophosphamide (IV CYC) in a multicenter clinical trial (UMIN000014344). In the present study, we evaluated the long-term outcomes and effects of induction therapy on the maintenance of remission. METHODS: All participants from our previous trial were followed up for > 5 years. Seventy-three other patients with anti-MDA5-positive DM-ILD from our institute were retrospectively integrated into the previous trial for further analysis. Sixty-eight patients achieved remission and survived for > 6 months. Based on the induction treatment, we classified the patients into 2 groups: (1) group T (n = 56), with triple combination therapy (GCs, CNIs, and IV CYC), and (2) group C (n = 12), with monotherapy/dual therapy. The recurrence-free and drug-withdrawal rates of immunosuppressive agents were compared. RESULTS: The overall survival and recurrence-free survival rates at 5 years were 100% for the participants in the previous trial. The 5-year cumulative withdrawal rates for CNIs and GCs were 70% and 53%, respectively. In a comprehensive analysis, the recurrence-free rates in group T were higher than those in group C (90% vs 56%; P < 0.05). The drug-withdrawal rates of CNIs and GCs at 10 years in group T were also higher than those in group C (79% vs 0% and 43% vs 0%, respectively; P < 0.05). CONCLUSION: Triple combination therapy in the induction phase can reduce the risk of recurrence and facilitate drug withdrawal in anti-MDA5-positive DM-ILD.

DOI： 10.3899/jrheum.2023-0371

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

To optimize patient prognosis, patient needs, including unmet needs, should be adequately assessed. However, such needs are more challenging to report and, consequently, more likely to go unmet compared with the needs reported by physicians. We aimed to determine the appropriate direction of future research on unmet medical needs in rheumatic diseases in Japan by conducting a literature review. We searched PubMed and Web of Science using 23 terms linked to unmet medical needs for major rheumatic diseases in Japan. Further, we collected articles on health-related quality of life and investigated the scales used for assessment, as well as whether the terms "unmet needs" or "unmet medical needs" were used. We identified 949 papers on 10 diseases, including systemic lupus erythematosus, systemic sclerosis, dermatomyositis, juvenile idiopathic arthritis, adult-onset Still's disease, antiphospholipid syndrome, mixed connective tissue disease, Takayasu arteritis, Sjögren's syndrome, and Behçet's disease; 25 of the 949 papers were selected for full-text review. Fifteen articles on five diseases were related to health-related quality of life. The term "unmet needs" was used in only one article. Six out of 15 studies used the 36-item short form survey, whereas the scales used in other studies differed. The optimal treatment plan determined by a physician may not necessarily align with the best interests of the patient. In clinical research, cross sectional and standardized indicators of health-related quality of life should be employed along with highly discretionary questionnaires to assess and optimize resource allocation in healthcare and simultaneously achieve patient-desired outcomes.

DOI： 10.1007/s00296-023-05425-z

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記述言語：日本語   出版者・発行元：(一社)日本臨床免疫学会  

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記述言語：日本語   出版者・発行元：(一社)日本臨床免疫学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Advanced systemic sclerosis-associated interstitial lung disease (SSc-ILD) can be treated with lung transplantation. There is limited data on lung transplantation outcomes in patients with SSc-ILD, in non-Western populations.We assessed survival data of patients with SSc-ILD, on the lung transplant (LT) waiting list, and evaluated post-transplant outcomes in patients from an Asian LT center. In this single-center retrospective study, 29 patients with SSc-ILD, registered for deceased LT at Kyoto University Hospital, between 2010 and 2022, were identified. We investigated post-transplant outcomes in recipients who underwent LT for SSc-ILD, between February 2002 and April 2022. Ten patients received deceased-donor LT (34%), two received living-donor LT (7%), seven died waiting for LT (24%), and ten survived on the waiting list (34%). Median duration from registration to deceased-donor LT was 28.9 months and that from registration to living-donor LT or death was 6.5 months. Analysis of 15 recipients showed improved forced vital capacity with a median of 55.1% at baseline, 65.8% at 6 months, and 80.3% at 12 months post-transplant. The 5-year survival rate for post-transplant patients with SSc-ILD was 86.2%. The higher post-transplant survival rate at our institute than previously reported suggests that lung transplantation is acceptable in Asian patients with SSc-ILD.

DOI： 10.1038/s41598-023-37141-w

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Decreased sialylation of IgG Fc glycans has been reported in autoimmune diseases, but its role in systemic lupus erythematosus (SLE) is not fully understood. In this study, we examined the pathogenicity of IgG desialylation and its association with Th17 in SLE using an animal model. METHODS: B6SKG mice, which develop lupus-like systemic autoimmunity due to the ZAP70 mutation, were used to investigate the pathogenicity of IgG desialylation. The proportion of sialylated IgG was compared between B6SKG and wild-type mice with or without β-glucan treatment-induced Th17 expansion. Anti-IL-23 and anti-IL-17 antibodies were used to examine the role of Th17 cells in IgG glycosylation. Activation-induced cytidine deaminase specific St6gal1 conditional KO (cKO) mice were generated to examine the direct effect of IgG desialylation. RESULTS: The proportions of sialylated IgG were similar between B6SKG and wild-type mice at steady state. However, IgG desialylation was observed after β-glucan-induced Th17 expansion, and nephropathy also worsened in B6SKG mice. Anti-IL-23/17 treatment suppressed IgG desialylation and nephropathy. Glomerular atrophy was observed in the cKO mice, suggesting IgG desialylation is directly involved in disease exacerbation. CONCLUSIONS: IgG desialylation contributes to the progression of nephropathy, which is ameliorated by blocking IL-17A or IL-23 in an SLE mouse model.

DOI： 10.1093/mr/road054

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記述言語：日本語   出版者・発行元：日本肺高血圧・肺循環学会  

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記述言語：日本語   出版者・発行元：日本肺高血圧・肺循環学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：BMJ  

Background

Growing evidence reveals a pathological role of somatic mutations in various autoimmune diseases, such as the mutation inUBA1in VEXAS syndrome,CARD11andKLHL6in cryoglobulinemic vasculitis, orSTAT3in Felty’s syndrome^[1]. Somatic mutations might also be involved in the pathogenesis of ANCA-associated vasculitis (AAV), which typically manifests in middle-aged and elderly individuals.

Objectives

We aimed to identify somatic mutations in patients with AAV.

Methods

We collected whole blood and obtained peripheral blood mononuclear cells (PBMCs) and neutrophils from patients with AAV in active-disease status (n=16), as well as from patients with other autoimmune diseases (n=8) as disease controls, and healthy subjects (n=10). In addition, we collected these specimens from 12 out of the 16 patients with AAV after remission induction. We performed RNA sequencing (RNA-seq) on the obtained cells and whole genome sequencing (WGS) on DNA extracted from the whole blood. Somatic mutations were detected by comparing the RNA and DNA sequences^[2].

Results

After stringent quality control, we identified 108 somatic mutations across 16 patients in active-disease status. The mean coverage of RNA-Seq at the mutation site was 100.9 ± 367.8 ×, and that of WGS was 14.4 ± 4.3 ×, while the mean allele fraction was 22.9 ± 20.5%. One or more mutations were detected in each of the 15 (93.8%) patients. The median mutation count of each patient was 4.0, which was not significantly different from disease controls or samples after remission induction. We mapped one gene to each of the 108 mutations, resulting in 95 genes in total. Mutations for six of the 95 genes were observed in two or more patients, and two of them were related to the ubiquitin system. Of the 108 mutations, 37 were missense, and 20 were predicted to be deleterious (combined annotation-dependent depletion Phred score &gt; 20). Among the 20 mutations, theHIST2H2ACmutation (NM_003517: p.L86P) in neutrophils was observed in two patients. To evaluate the functional outcome of the 20 mutations, we analysed the data on knocking out the corresponding genes using CRISPR in K562 cells^[3]. The results showed that the expression of genes related to antigen presentation was increased inHEATR1andRPL18knockouts. When we followed up with 12 of the 16 patients after remission induction, 81.4% of the somatic mutations were no longer detected. Additionally, 91.7% of the deleterious mutations disappeared.

Conclusion

We found somatic mutations with potential pathological effects in some patients with AAV exhibiting active-disease status. Notably, the majority of these mutations were not detected after remission induction.

References

[1]Mustjoki, S. &amp; Young, N. S. Somatic Mutations in ‘Benign’ Disease. N. Engl. J. Med. 384, 2039–2052 (2021).

[2]Yizhak, K. et al. RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science 364, (2019).

[3]Replogle, J. M. et al. Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq. Cell 185, 2559-2575.e28 (2022).

Acknowledgements

The present study was supported in part by JSPS KAKENHI. (Grant No. 19H03209).

Disclosure of Interests

None Declared.

DOI： 10.1136/annrheumdis-2023-eular.243

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Systemic lupus erythematosus (SLE) is an intractable disease characterized by autoantibody production and autoreactive B and T cell proliferation. Although several studies have revealed multiple genetic and environmental associations, the underlying mechanisms remain unknown. METHODS: We performed proteomics and transcriptomics using liquid chromatography-mass spectrometry and DNA microarray, using peripheral blood B cells from patients with SLE, and healthy controls (HC). We explored molecules associated with the pathophysiology of SLE by flow cytometry and B cell stimulation assay. RESULTS: We identified for the first time that expression of both S100A8 protein and mRNA were markedly upregulated in SLE B cells. The results obtained using flow cytometry showed that S100A8 was highly expressed on the surface of B cells of patients with active SLE (MFI; HC 102.5 ± 5.97, stable SLE 111.4 ± 12.87, active SLE 586.9 ± 142.9), and S100A8 on the cell surface was decreased after treatment (MFI; pre-treat 1094.5 ± 355.38, post-treat 492.25 ± 247.39); therefore, it is suggested that S100A8 may be a marker for disease activity. The mRNA expression of S100A8 was particularly upregulated in memory B cells of SLE (56.68 fold higher than HC), suggesting that S100A8 may be mainly secreted by memory B cells in the pathogenesis of SLE. CONCLUSIONS: Our results imply that the S100A8 proteins secreted from memory B cells may stimulate granulocytes and monocytes through pattern recognition receptors, activate the innate immune system, and are involved in the pathogenesis of SLE.

DOI： 10.1186/s13075-023-03057-z

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出版者・発行元：Research Square Platform LLC  

Abstract

We conducted a Japanese GWAS for systemic sclerosis (SSc) comprising 1,428 cases and 112,599 controls, the largest Asian GWAS for SSc ever, and identified three novel signals. The lead SNP in FCGR/FCRL region had a strong effect size (OR 2.05, P = 4.9×10⁻¹¹). The complete LD SNP, rs10917688, was found in a cis-regulatory element and a part of binding motifs for IRF8. IRF8 was a significant locus in the European GWAS and rs10917688 showed an association only in the presence of the risk allele of IRF8 in Japanese. rs10917688 was marked with H3K4me1 in primary B cells, and the heritability was enriched in active histone marks of primary B cells. A meta-analysis with the latest European GWAS found additional 30 significant loci including three novel signals. PRS constructed with the effect sizes of the meta-analysis indicated potential portability of genetic associations beyond populations (AUC: 0.593). The fitting of PRS was improved by further prioritizing the top 5% SNPs of IRF8 biding sites in B cells, underscoring common genetic architecture across populations and critical roles of B cells and IRF8 for SSc development.

DOI： 10.21203/rs.3.rs-2712663/v1

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その他リンク： https://www.researchsquare.com/article/rs-2712663/v1.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/mr/road035

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Abstract

Objectives

Although the systemic lupus erythematosus disease activity score (SLE-DAS) and its definitions to classify disease activity have been recently developed to overcome the drawbacks of the SLE Disease Activity Index 2000 (SLEDAI-2K), the performance of the SLE-DAS for patient-reported outcomes (PROs) has not been fully examined. We aimed to compare SLE-DAS with SLEDAI-2K and validate the classifications of disease activity based on SLE-DAS in terms of PROs.

Methods

We assessed generic quality of life (QoL) using the Medical Outcome Survey 36-Item Short-Form Health Survey (SF-36), disease-specific QoL using the Lupus Patient-Reported Outcome tool (LupusPRO), burden of symptoms using the SLE Symptom Checklist (SSC), patient global assessment (PtGA), and physician global assessment (PhGA).

Results

Of the 335 patients with SLE, the magnitudes of the mean absolute error, root mean square error, Akaike Information Criterion, and Bayesian Information Criterion were comparable for most PROs between the SLE-DAS and SLEDAI-2K. In contrast, SLEDAI-2K had a higher predictive value for health-related QoL of LupusPRO and PtGA than SLE-DAS. Low disease activity, Boolean and index-based remission, and categories of disease activity (remission, mild, and moderate/severe activity) were significantly associated with health-related QoL in LupusPRO, SSC, and PhGA, but not SF-36 or PtGA.

Conclusion

No clear differences were identified in the use of the SLE-DAS over the SLEDAI-2K in assessing PROs in patients with SLE. The classification of disease activity based on the SLE-DAS was validated against several PROs. SLE-DAS and its categories of disease activity effectively explain some of the PROs.

DOI： 10.1093/rheumatology/kead132

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Public Library of Science (PLoS)  

Immunoglobulin (Ig) G4 is an IgG subclass that can exhibit inhibitory functions under certain conditions because of its capacity to carry out Fab-arm exchange, inability to form immune complexes, and lack of antibody-dependent and complement-dependent cytotoxicity. Although several diseases have been associated with IgG4, its role in the disease pathogeneses remains unclear. Since mice do not express an IgG subclass that is identical to the human IgG4 (hIgG4), we generated hIGHG4 knock-in (KI) mice and analyzed their phenotypes. To preserve the rearrangement of the variable, diversity, and joining regions in the IGH gene, we transfected a constant region of the hIGHG4 gene into C57BL/6NCrSlc mice by using a gene targeting method. Although the mRNA expression of hIGHG4 was detected in the murine spleen, the serum level of the hIgG4 protein was low in C57BL/6-IgG4KI mice. To enhance the production of IgG4, we established an MRL/lpr-IgG4KI mice model by backcrossing. These mice showed a high IgG4 concentration in the sera and increased populations of IgG4-positive plasma cells and CD3⁺B220⁺CD138⁺ T cells in the spleen. Moreover, these mice showed aggravated inflammation in organs, such as the salivary glands and stomach. The MRL/lpr-IgG4KI mouse model established in the present study might be useful for studying IgG4-related disease, IgG4-type antibody-related diseases, and allergic diseases.

DOI： 10.1371/journal.pone.0279389

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Abstract

Objectives

Osteoporosis and compression fractures of the lumbar spine are some of the major adverse effects of glucocorticoid therapy in patients with systemic lupus erythematosus (SLE). This study examined the association between bone mineral density, bone turnover markers, presence of vertebral fractures, and Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI) in SLE patients.

Methods

This was a cross-sectional study of 246 outpatients with SLE at the Kyoto University Hospital. Lumbar and femoral BMD were measured with dual-energy X-ray absorptiometry, and presence of vertebral fractures was determined using X-ray, CT, or MR imaging.

Results

On multiple regression analysis, high lumbar and femoral T-scores were both associated with concomitant use of hydroxychloroquine (p = 0.018 and p = 0.037, respectively), no use of bisphosphonate or denosumab (p = 0.004 and p = 0.038, respectively), high body mass index (p &amp;lt; 0.001), and low bone-specific alkaline phosphatase (BAP) level (p = 0.014 and p = 0.002, respectively). Vertebral fractures showed a significant association with SDI score (p &amp;lt; 0.001) and femoral T-score (p &amp;lt; 0.001).

Conclusions

Vertebral fracture was associated with SLE-associated organ damage and serum BAP level is a potentially useful marker for osteoporosis monitoring in SLE patients.

DOI： 10.1093/mr/road014

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Abstract

Objective

We previously reported that rheumatoid factor (RF) recognized the IgG heavy chain (IgGH)/RA-susceptible HLA class II molecule complex. In the present study, we investigated the molecular mechanisms underlying HLA binding to and the RF recognition of IgGH.

Methods

We synthesized various types of IgGH segments, including VH, CH1, CH2, and CH3, and transfected them with or without HLA class II molecules into the HEK 293 T cell line. IgGH single domains linked with the HLA-Cw3 peptide, which binds to the binding groove of the HLA class II molecule, were also synthesized. The expression of IgGH domains on the cell surface and their recognition by RF were examined using flow cytometry.

Results

Flag-tagged IgGH segments containing CH1 (CH1, VH-CH1, CH1-CH2, VH-CH1-CH2, CH1-CH2-CH3, and VH-CH1-CH2-CH3) were clearly presented on the cell surface by HLA-DR4, while segments without the CH1 domain were expressed at a low level, and the CH3 single domain was only weakly detected on the cell surface, even with HLA-DR4. We then transfected IgGH single domains linked to the Cw3 peptide together with HLA-DR4 and showed that RF-containing sera from RA patients only recognized the CH3 domain and none of the other single domains. When various segments without the Cw3 peptide were transfected with HLA-DR4, only the CH1-CH2-CH3 segment and full-length IgGH were detected by the sera of RA patients.

Conclusion

The CH1 domain of IgGH binds to the RA-susceptible HLA-DR molecule and is expressed on the cell surface. RF specifically recognizes the CH3 domain of the IgGH/HLA-DR4 complex.

DOI： 10.1093/rheumatology/kead024

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Autoimmune diseases are often accompanied by acute exacerbation. However, the mechanism underlying systemic lupus erythematosus (SLE) flares remains unclear. We investigated whether short-term enteric Toll-like receptor 7 (TLR7) stimulation can exacerbate SLE using B6SKG mice, which spontaneously develop SLE due to a mutation in the zeta‒chain‒associated protein kinase 70 (Zap70) gene. Imiquimod (IMQ) or phosphate-buffered saline (PBS) were orally administered on B6WT and B6SKG mice every other day for 2 weeks. SLE exacerbation was assessed via fluorescent immunohistochemical staining of glomeruli for IgG and C3, hematoxylin and eosin staining of kidneys, and enzyme-linked immunosorbent assay for antinuclear antibody (ANA). Flow cytometry was used to evaluate germinal center B cells (GCBs), plasma cells, follicular helper T cells (Tfhs), regulatory T cells (Tregs), effector T cells (Th1s and Th17s), plasmacytoid dendritic cells (pDCs), conventional dendritic cells (cDCs), and macrophages (Mφs) in spleens. Oral administration of IMQ every other day for 2 weeks resulted in exacerbation of splenomegaly, increased IgG and C3 deposition in glomeruli, and increased ANA production in the B6SKG IMQ (SKG-IMQ) group compared to the B6SKG PBS (SKG-PBS) group; the percentages of GCBs, plasma cells, Tfhs, Th1s, pDCs, and Mφs were also increased in the SKG-IMQ group. Splenomegaly, IgG, and C3 deposition in glomeruli, and the percentages of GCBs, plasma cells, Tfhs, and Th1s were enhanced in SKG-IMQ mice compared with B6SKG mice topically treated with IMQ (SKG-ear-IMQ). Oral TLR7 stimulation in a Zap70 genetic mutation background can cause acute exacerbations of SLE. Key Points • The mechanism of SLE flares is not well understood. • We have created a model that causes short-term SLE exacerbations in mice with a genetic background. • IMQ administered orally causes more SLE in mice than transdermally.

DOI： 10.1007/s10067-022-06467-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Schnitzler syndrome is a rare disorder with chronic urticaria, and there is no report summarizing the current status in Japan. METHODS: A nationwide survey of major dermatology departments in Japan was conducted in 2019. We further performed a systematic search of PubMed and Ichushi-Web, using the keywords "Schnitzler syndrome" and "Japan" then contacted the corresponding authors or physicians for further information. RESULTS: Excluding duplicates, a total of 36 clinically diagnosed cases were identified from 1994 through the spring of 2022, with a male to female ratio of 1:1. The median age of onset was 56.5 years. It took 3.3 years from the first symptom, mostly urticaria, to reach the final diagnosis. The current status of 30 cases was ascertained; two patients developed B-cell lymphoma. SchS treatment was generally effective with high doses of corticosteroids, but symptoms sometimes recurred after tapering. Colchicine was administered in 17 cases and was effective in 8, but showed no effect in the others. Tocilizumab, used in six cases, improved laboratory abnormalities and symptoms, but lost its efficacy after several years. Rituximab, used in five cases, was effective in reducing serum IgM levels or lymphoma mass, but not in inflammatory symptoms. Four cases were treated with IL-1 targeting therapy, either anakinra or canakinumab, and achieved complete remission, except one case with diffuse large B-cell lymphoma. CONCLUSIONS: Since Schnitzler syndrome is a rare disease, the continuous collection and long-term follow-up of clinical information is essential for its appropriate treatment and further understanding of its pathophysiology.

DOI： 10.1016/j.alit.2022.11.004

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: We aimed to identify associations between patterns of large-vessel lesions of large-vessel giant cell arteritis (LV-GCA) and treatment outcomes. METHODS: We extracted data on 68 newly-diagnosed patients with LV-GCA from a retrospective, multi-centric, nationwide registry of GCA patients treated with glucocorticoids between 2007 and 2014. Patients with aortic lesions were identified based on findings from contrast-enhanced computed tomography (CT), magnetic resonance imaging, or positron emission tomography-CT (group 2, n=49). Patients without aortic lesions were subdivided into LV-GCA with or without subclavian lesions defined as group 1 (n=9) or group 3 (n=10), respectively. Primary outcome evaluation was failure to achieve clinical remission by week 24 and/or relapse within 104 weeks. RESULTS: The mean age and proportion of patients with cranial lesions and polymyalgia rheumatica in group 2 was numerically lower than in the other two groups. Large-vessel lesions in group 3 included carotid, pulmonary, renal, hepatic or mesenteric lesions. The cumulative rate of poor treatment outcomes over two years was 11.1%, 55.3%, and 88.0% in groups 1, 2, and 3, respectively (by Kaplan-Meier analysis). The mean time to poor outcome was significantly different between the groups. CONCLUSIONS: Classification by subclavian and aortic lesions may be useful to determine treatment strategy.

DOI： 10.1093/mr/roac122

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/rheumatology/keac569

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記述言語：日本語   出版者・発行元：(一社)日本小児リウマチ学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Numerous case reports have referred to new onset or flare of SLE after SARS-CoV-2 messenger RNA (mRNA) vaccines. Several observational studies showed that the short-term flare rate of SLE after SARS-CoV-2 vaccination is low. However, well-controlled clinical surveys are unavailable and the medium-term impact of the SARS-CoV-2 mRNA vaccines against the flare of SLE is uncertain. Therefore, we aimed to analyse the association between vaccination and medium-term subjective and objective disease activities of SLE and flares using matched pair methods. METHODS: Altogether, 150 patients with SLE from the Kyoto Lupus Cohort were included. Patients who received two doses of the SARS-CoV-2 mRNA vaccines were 1:1 matched with unvaccinated patients based on the first vaccination date. The outcome measures were the SLE Disease Activity Index-2000 (SLEDAI-2K), the Japanese version of the SLE Symptom Checklist Questionnaire (SSC-J) and the Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI flare index at 30, 60 and 90 days after vaccination. RESULTS: SLEDAI-2K levels were not significantly different in vaccinated and unvaccinated patients with SLE at 30, 60 and 90 days after the second vaccination (adjusted estimate (95% CI): 30 days: -0.46 (-1.48 to 0.56), p=0.39; 60 days: 0.38 (-0.64 to 1.40), p=0.47; 90 days: 0.40 (-0.54 to 1.34), p=0.41). Similar results were observed in the SSC-J score (adjusted estimate (95% CI), 30 days: 0.05 (-1.46 to 1.56), p=0.95; 60 days: -0.63 (-2.08 to 0.82), p=0.40; 90 days: 0.27 (-1.04 to 1.58), p=0.69) and flare index (adjusted OR (95% CI), 30 days: 0.81 (0.36 to 1.85), p=0.62; 60 days: 1.13 (0.50 to 2.54), p=0.77; 90 days: 0.85 (0.32 to 2.26), p=0.74). CONCLUSION: SARS-CoV-2 vaccination did not significantly influence the medium-term subjective and objective disease activities or flares of SLE until 90 days after the second vaccination.

DOI： 10.1136/lupus-2022-000727

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Spondyloarthritis (SpA) is an autoimmune and autoinflammatory musculoskeletal disease characterised by systemic enthesitis. Recent research has focused on subclinical inflammatory bowel disease (IBD) in SpA pathogenesis. SKG mice, harbouring the Zap70 W163C mutation, increase autoreactive Th17 cells intrinsically, and in a conventional environment, they exhibit spontaneous arthritis with fungal factors. Under SPF conditions, they show SpA features, including enteritis, after peritoneal injection of β-1,3-glucan. This study aimed to clarify whether oral dextran sulfate sodium (DSS) administration, utilised in IBD model mice, can provoke SpA features in SKG mice under SPF conditions, focusing on the relationship between gut microorganisms and SpA pathogenesis. METHODS: BALB/c and SKG mice were administered oral DSS, and their body weights, arthritis, and enthesitis scores were recorded. In another cohort, antibiotics (meropenem and vancomycin) or an anti-fungal agent (amphotericin B) was administered orally before DSS administration. The splenic Th1 and Th17 cell populations were examined before and after DSS administration using flow cytometry. Furthermore, the amount of circulating bacterial DNA in whole blood was measured by absolute quantitative polymerase chain reaction (qPCR), and the number and characteristics of bacterial species corresponding to these circulating DNA were analysed by next-generation sequencing (NGS). RESULTS: Ankle enthesitis as a peripheral SpA feature was elicited in half of DSS-administered SKG mice, and none of the BALB/c mice. Pre-administration of antibiotics suppressed enthesitis, whilst an anti-fungal agent could not. Th1 and Th17 cell levels in the spleen increased after DSS administration, and this was suppressed by pre-administration of antibiotics. SKG mice have a larger amount of bacterial DNA in whole blood than BALB/c mice before and 1 day after the initiation of DSS administration. The number of bacterial species in whole blood increased after DSS administration in BALB/c and SKG mice. Some genera and species significantly specific to the DSS-treated SKG mouse group were also detected. CONCLUSION: Oral DSS administration alone elicited peripheral enthesitis in SKG mice with bacterial translocation accompanied by increased splenic Th1 and Th17 cell levels. Pre-administration of antibiotics ameliorated these DSS-induced SpA features. These findings suggest that intestinal bacterial leakage plays a pivotal role in SpA pathogenesis.

DOI： 10.1186/s13075-022-02844-4

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記述言語：日本語   出版者・発行元：日本肺高血圧・肺循環学会・日本小児肺循環研究会  

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記述言語：日本語   出版者・発行元：日本肺高血圧・肺循環学会・日本小児肺循環研究会  

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記述言語：日本語   出版者・発行元：日本肺高血圧・肺循環学会・日本小児肺循環研究会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Intestinal amoebiasis is caused by Entamoeba histolytica (E. histolytica) and is characterised by cecal lesions, multiple lesions, aphthae, and multiple exudative erosions. Intestinal Behçet's disease (BD) is a chronic inflammatory disorder that is characterised by multiple ulcers. Although the aetiologies of these two bowel diseases are unrelated, they are difficult to distinguish because they present similarly with inflammation and ulcers, especially if evidence of specific pathogens is not detected. Herein, we report a case of intestinal amoebiasis in a patient with BD. The patient underwent colonoscopy four times before intestinal amoebiasis was diagnosed. As intestinal BD was initially suspected, she received high-dose glucocorticoid therapy, which exacerbated her condition. Following exacerbation, she underwent colonoscopy, and E. histolytica was revealed. Deliberate care should be taken to distinguish between intestinal amoebiasis and intestinal BD, as the appropriate treatments for these diseases are entirely different.

DOI： 10.1093/mrcr/rxac028

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although the survival rates of patients with relapsing polychondritis (RP) have increased remarkably, the high recurrence rate remains a significant concern for physicians and patients. This retrospective study aimed to investigate the risk factors for RP recurrence. METHODS: Patients with RP who presented to Kyoto University Hospital from January 2000 to March 2020 and fulfilled Damiani's classification criteria were included. Patients were classified into recurrence and non-recurrence groups. Risk factors for RP recurrence were analysed using a Cox proportional hazards model, and Kaplan-Meier survival curves were drawn. RESULTS: Thirty-four patients were included. Twenty-five patients (74%) experienced 64 recurrences (mean: 2.56 recurrences per patient). The median duration before the first recurrence was 202 [55-382] days. The median prednisolone dose at the initial recurrence was 10 [5-12.75] mg/day. Tracheal involvement was significantly more frequent in the recurrence group at the initial presentation (44.0% vs. 0.0%, p=0.0172) than in the non-recurrence group, and pre-treatment C-reactive protein levels were significantly higher in the recurrence group than in the non-recurrence group (4.7 vs 1.15 mg/dL, p=0.0024). The Cox proportional hazards model analysis revealed that tracheal involvement (hazard ratio [HR] 4.266 [1.535-13.838], p=0.0048), pre-treatment C-reactive protein level (HR 1.166 [1.040-1.308], p=0.0085), and initial prednisolone monotherapy (HR 4.443 [1.515-16.267], p=0.0056) may be associated with recurrence. The median time before the initial recurrence was significantly longer in patients who received combination therapy with prednisolone and immunosuppressants or biologics (400 vs. 70 days, p=0.0015). CONCLUSIONS: Tracheal involvement, pre-treatment C-reactive protein level, and initial prednisolone monotherapy were risk factors for recurrence in patients with RP. Initial combination therapy with prednisolone and immunosuppressants may delay recurrence.

DOI： 10.1186/s13075-022-02810-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Relapsing polychondritis (RP) is a rare inflammatory disease characterized by recurrent inflammation and destruction of cartilaginous tissues. RP has characteristics of autoimmune disease and some reports have noted co-occurrence with autoimmune thyroid disease (AITD), consisting of Graves' disease (GD) and Hashimoto thyroiditis (HT). However, there have been no detailed studies on the co-occurrence of RP and AITD. In this study, we aimed to determine whether patients with RP tend to be complicated with AITD. We also analyzed the clinical and genetic profiles of patients in whom these diseases co-occur. METHODS: We recruited 117 patients with RP and reviewed their medical records. Furthermore, we genotyped Human Leucocyte Antigen (HLA)-A, B Cw, DRB1, DQB1, and DPB1 alleles for 93 of the 117 patients. The prevalence of AITD among the patients with RP was compared with that among the general Japanese population. We also analyzed the clinical and genetic features of the patients with both RP and AITD. RESULTS: The prevalence of GD among the patients with RP was 4.3% (5 among 117 patients), significantly higher than that among Japanese (0.11%) (p = 2.44 × 10-7, binomial test). RP patients with GD tended to have nasal involvement (p = 0.023) (odds ratio (OR) 2.58) and HLA-DPB1*02:02 (p = 0.035, OR 10.41). We did not find significant enrichment of HT in patients with RP. CONCLUSIONS: Patients with RP appear to be at elevated risk of GD. Nasal involvement and HLA-DPB1*02:02 characterize the subset of RP patients with GD, which may guide attempts to characterize a distinct subtype of RP for precision medicine.

DOI： 10.1186/s13023-022-02261-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: T cell receptor (TCR) signaling abnormalities and gut dysbiosis are thought to be involved in the development of systemic lupus erythematosus (SLE). However, it is not known whether these mechanisms are interrelated. This study was undertaken to explore the impact of defective TCR signaling on microbiota-driven immune responses and the consequent triggering of systemic autoimmunity. METHODS: The responses of B6SKG mice harboring a mutation in ZAP-70 leading to spontaneous development of SLE were evaluated under specific pathogen-free (SPF) and germ-free (GF) conditions. The gut microbiome was analyzed using 16S ribosomal RNA sequencing. Secretory IgA production in the gut and follicular helper T (Tfh) cell development in the spleen and Peyer's patches were analyzed. Interleukin-17 (IL-17)-deficient mice and segmented filamentous bacteria (SFB)-specific TCR-transgenic mice were used to examine the role of IL-17 and thymic selection. RESULTS: SLE development in B6SKG mice was significantly more attenuated under GF conditions than under SPF conditions. The gut microbiota in B6SKG mice was altered, which was associated with the expansion of SFB and consequent development of SLE by driving Th17 cell differentiation, which was in turn blunted by IL-17 deficiency. Notably, although systemic Tfh development and autoantibody IgG response were enhanced, local gut Tfh and IgA responses were impaired. Moreover, experiments in SFB-specific TCR-transgenic mice revealed that this differential response was caused by altered thymic selection of self- and microbiota-reactive TCR because of defective TCR signaling. CONCLUSION: Our findings indicate that defective TCR signaling alters the gut microbiota and promotes systemic autoimmunity by driving Th17 cell differentiation.

DOI： 10.1002/art.42016

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: To eliminate the disparity and maldistribution of physicians and medical specialty services, the development of diagnostic support for rare diseases using artificial intelligence is being promoted. Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a rare disorder often requiring special knowledge and experience to diagnose. In this study, we investigated the possibility of differential diagnosis of IgG4-RD based on basic patient characteristics and blood test findings using machine learning. METHODS: Six hundred and two patients with IgG4-RD and 204 patients with non-IgG4-RD that needed to be differentiated who visited the participating institutions were included in the study. Ten percent of the subjects were randomly excluded as a validation sample. Among the remaining cases, 80% were used as training samples, and the remaining 20% were used as test samples. Finally, validation was performed on the validation sample. The analysis was performed using a decision tree and a random forest model. Furthermore, a comparison was made between conditions with and without the serum IgG4 concentration. Accuracy was evaluated using the area under the receiver-operating characteristic (AUROC) curve. RESULTS: In diagnosing IgG4-RD, the AUROC curve values of the decision tree and the random forest method were 0.906 and 0.974, respectively, when serum IgG4 levels were included in the analysis. Excluding serum IgG4 levels, the AUROC curve value of the analysis by the random forest method was 0.925. CONCLUSION: Based on machine learning in a multicenter collaboration, with or without serum IgG4 data, basic patient characteristics and blood test findings alone were sufficient to differentiate IgG4-RD from non-IgG4-RD.

DOI： 10.1186/s13075-022-02752-7

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The mature form of sterol regulatory element-binding protein (SREBP)1 is a transcription factor involved in lipid synthesis, which participates in toll like receptor 4-triggered inflammatory pathways during the resolution phase of inflammation in macrophages. SREBP1 has thus attracted interest as a candidate target molecule for ameliorating inflammation. Fatostatin is a small molecule that inhibits the maturation and function of SREBP, and its role in regulating inflammation is poorly understood. To evaluate the anti-inflammatory effect of fatostatin, we compared body weight, footpad and hock dimensions, and arthritis scores between K/BxN serum-induced arthritis mice treated with fatostatin and those treated with dimethyl sulfoxide as the vehicle control. We performed hematoxylin and eosin staining of joints of distal paws to assess tissue inflammation. Moreover, inflammatory cytokine production levels and cell viability were measured in lipopolysaccharide-responsive human embryonic kidney 293 cells (293/hTLR4A-MD2-CD14 cells) after fatostatin administration. In K/BxN serum-induced arthritis mice, fatostatin treatment significantly reduced the arthritis scores and hyperplasia. In vitro analysis revealed that fatostatin significantly inhibited the secretion of inflammatory cytokines from cells activated with lipopolysaccharide, without affecting cell viability. This is the first study to demonstrate that fatostatin is an anti-inflammatory agent that modulates the processing of lipid transcription factors without affecting cell viability. Accordingly, the study reveals the potential of anti-inflammatory therapeutics that link lipid regulation and inflammation.

DOI： 10.1002/2211-5463.13364

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Recent advances in imaging revealed that giant cell arteritis (GCA) is frequently associated with large vessel involvement (LVI), but they may also contribute to earlier diagnosis and treatment of LV-GCA. We aimed to compare clinical characteristics of GCA with or without LVI and evaluate its association with clinical outcomes. METHOD: We retrospectively reviewed the medical records of 36 patients with GCA in Kyoto University Hospital. RESULTS: Eighteen patients each were assigned to the LVI(+) and LVI(-) groups. Five-year survival rates in the LVI(+) group was better than in the LVI(-) group (P = 0.034), while five-year relapse-free survival rates were similar between the groups (P = 0.75). The LVI(+) group required lower doses of glucocorticoid at month 6 (P = 0.036). Disease activity evaluated with the Birmingham Vasculitis Activity Score at disease onset was higher in the LVI(-) group (P = 0.014), and the Vasculitis Damage Index score examined at the last visit was higher in the LVI(-) group (P = 0.011). CONCLUSION: GCA without LVI had more active disease, severer vascular damage, and worse survival, possibly because of ophthalmic complications and their greater glucocorticoid requirement. Our results revisit the impact of cranial manifestations on disease severity and morbidity.

DOI： 10.1093/mr/roac013

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To investigate the association of autoantibodies with scleroderma renal crisis (SRC) among Japanese patients. METHODS: The clinical characteristics and mortality of 330 patients with systemic sclerosis (SSc) at Kyoto University Hospital were retrospectively analyzed, focusing on anti-topoisomerase I, anti-centromere, anti-RNA polymerase III (RNAPIII), and anti-U1-RNP. Logistic regression analyses were performed to examine the association of autoantibodies with the development and mortality of SRC. RESULTS: SRC was observed in 24 out of 330 SSc patients, including anti-topoisomerase I (n = 12/24, 50%), anti-RNAPIII (n = 7/24, 29%), anti-U1-RNP (n = 5/24, 21%), and anti-centromere (n = 3/24, 13%). Anti-U1-RNP (odds ratio [95% confidence interval], 3.63 [1.11-10.2]), anti-topoisomerase I (3.22 [1.37-7.57]), and anti-RNAPIII (3.29 [1.16-8.70]) were associated with the development of SRC. Furthermore, anti-topoisomerase I (6.00 [1.11-41.1]) was associated with the 1-year mortality of SRC. The 1-year survival rate after the onset of SRC among all patients and those positive for anti-topoisomerase I was 54% and 33%, respectively. In contrast, the survival rate in patients negative for anti-topoisomerase I was 75%, of which the survival rate of patients positive for anti-RNAPIII and anti-centromere was 83% and 100%, respectively. CONCLUSION: Specific SSc-related autoantibodies were associated with the morbidity and mortality of SRC.

DOI： 10.1093/rheumatology/keac047

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Pulmonary artery involvement (PAI) in Takayasu arteritis (TAK) can lead to severe complications, but the relationship between the two has not been fully clarified. METHODS: We retrospectively investigated 166 consecutive patients with TAK who attended Kyoto University Hospital from 1997 to 2018. The demographic data, clinical symptoms and signs, comorbidities, treatments, and imaging findings were compared between patients with and without PAI. TAK was diagnosed based on the American College of Rheumatology Classification Criteria (1990) or the Japanese Clinical Diagnostic Criteria (2008). PAI was identified using enhanced computed tomography, magnetic resonance imaging, or lung scintigraphy. RESULTS: PAI was detected in 14.6% (n = 24) of total TAK patients. Dyspnea (25.0% vs. 8.6%; p = 0.043), pulmonary arterial hypertension (PAH) (16.7% vs. 0.0%; p < 0.001), ischemic heart disease (IHD) (29% vs. 9.3%; p = 0.018), respiratory infection (25.0% vs. 6.0%; p = 0.009), and nontuberculous mycobacteria (NTM) infection (20.8% vs. 0.8%; p < 0.001) were significantly more frequent, and renal artery stenosis (0% vs. 17%; p = 0.007) was significantly less frequent in TAK patients with PAI than in those without PAI. PAI and biologics were risk factors for NTM. CONCLUSIONS: TAK patients with PAI more frequently have dyspnea, PAH, IHD, and respiratory infection, including NTM, than TAK patients without PAI.

DOI： 10.1186/s13075-021-02675-9

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To develop a proposal for remission criteria and a framework for a treat-to-target (T2T) algorithm for Takayasu arteritis (TAK). METHODS: A study group of the large-vessel vasculitis group of the Japanese Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS) consists of 10 rheumatologists, 5 cardiologists, 1 nephrologist, 1 vascular surgeon, 1 cardiac surgeon, and 2 pediatric rheumatologists. A Delphi survey of remission criteria items was circulated among the study group over 4 reiterations. To develop the T2T algorithm, the study group conducted four face-to-face meetings and two rounds of Delphi together with 3 patients. RESULTS: Initial literature review resulted in a list of 117 candidate items for remission criteria, of which 56 items with a mean score of ≥4 (0-5) were extracted including disease activity domains and treatment/comorbidity domains. The study group provided six overarching principles for the T2T algorithm, two recommendations on treatment goals, five on evaluation of disease activity and imaging findings including PET-CT, and two on treatment intensification. CONCLUSIONS: We developed a T2T algorithm and proposals for standardized remission criteria by means of a Delphi exercise. These will guide future evaluation of different TAK treatment regimens.

DOI： 10.1093/mr/roab081

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Schnitzler syndrome is characterized by chronic urticarial rash, neutrophilic dermal infiltrate, recurrent fever, bone pain, elevated C-reactive protein, and neutrophilic leukocytosis. The pathophysiology of Schnitzler syndrome is unknown, but it is considered to be an acquired form of an autoinflammatory disease because of the resemblance to clinical phenotypes of cryopyrin-associated periodic syndrome, in which a gain-of-function mutation in NLRP3 causes overexpression of interleukin (IL)-1β. Schnitzler syndrome is generally accompanied by a monoclonal immunoglobulin (Ig)M gammopathy with a long-term risk of lymphoproliferation that is possibly associated with an MYD88 mutation. Herein, we present the following four patients with Schnitzler syndrome: a 63-year-old woman; a 65-year-old man; a 43-year-old woman; and a 63-year-old woman. Each patient fulfilled the Strasbourg diagnostic criteria, but none of the patients had any mutation in NLRP3 or MYD88 detected in their peripheral blood. Although approved treatment options for Schnitzler syndrome are lacking, our patients were treated with IL-1-targeted therapy (anakinra or canakinumab) or anti-IL-6 (tocilizumab). The acute inflammatory clinical manifestations improved completely with canakinumab and partially with anakinra and tocilizumab, but the serum IgM levels were gradually increased in all patients, even during treatment. To determine whether treatment with anti-IL-1β or IL-6 prevents conversion to a hematopoietic disorder, further collection of cases and long-term follow-up will be needed.

DOI： 10.1111/1346-8138.16124

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本臨床免疫学会  

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記述言語：日本語   出版者・発行元：(一社)日本臨床免疫学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経治療学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.ensci.2021.100351

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: The present study aimed to clarify comprehensive relationships among the clinical variables of systemic lupus erythematosus (SLE). METHODS: We retrospectively surveyed 32 clinical variables in 581 patients and conducted comprehensive association studies among SLE clinical phenotypes. A univariate analysis of all possible combinations was performed, and the results of phenotypic correlations were reduced into two dimensions. We also created a regression formula using L1 regularisation (LASSO) to calculate the probability of exhibiting each phenotype. RESULTS: The univariate analysis identified 26 correlations, including multiple phenotypes with low complement. Some unpredicted correlations were identified, including fever and the anti-Sm antibody (odds ratio; OR = 2.3, p = 1.6 × 10-5) or thrombocytopenia and psychosis (OR = 3.7, p = 3.2 × 10-5). The multivariate analysis accurately estimated the probability of exhibiting each phenotype (area under the curve > 0.7) in 10 out of 20 phenotypes. CONCLUSIONS: The present results show the phenotypic architecture of SLE and represent a model for estimating the probability of exhibiting each phenotype. They also offer insights into the pathology of SLE and estimating the probability of the onset of new phenotypes in clinical practice.

DOI： 10.1093/mr/roab020

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/rheumatology/keab184

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Neutropenia is a common adverse event of tocilizumab (TCZ) in rheumatoid arthritis (RA) patients; however, the association between the decrease in neutrophil counts and the TCZ clinical efficacy remains inconclusive. This study aimed to examine whether TCZ-induced neutrophil decrease at 1 month predicts clinical remission within 1 year. We reviewed medical records of RA patients initiating TCZ between May 2011 and September 2019 in our hospital. The Clinical Disease Activity Index (CDAI) was evaluated at baseline (before initiating TCZ) and 1, 3, 6, and 12 months after administration. Clinical remission was defined when CDAI decreased ≤ 2.8. The ratio of neutrophil counts 1 month after initiating TCZ to those at baseline (neutrophil ratio) was also calculated. Among 255 TCZ-treated patients, 169 with valid CDAI and neutrophil counts were enrolled (with median age of 60 years and 79% females). Rheumatoid factor and anti-cyclic citrullinated peptide antibody were positive in 75% and 83%, respectively, and 56% of the patients had concomitant methotrexate (median dose: 8 mg/week). Multivariate logistic regression analysis suggested baseline CDAI (odds ratio (OR) 0.96, p = 0.045), concomitant PSL (OR 0.42, p = 0.030), and the neutrophil ratio (OR 0.19, p = 0.011) as predictors of CDAI remission. Neutrophil ratio ≤ 0.8 was associated with achieving remission (Fisher's exact test, p = 0.02) with no apparent increase of severe infection. More than 20% reduction of neutrophil count 1 month after initiating TCZ predicts clinical remission within 1 year at an early treatment phase.

DOI： 10.1007/s00296-021-04944-x

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

HLA-B*52 is an established genetic factor in Takayasu arteritis (TAK). Recently, single nucleotide polymorphisms (SNPs) in IL12B (rs6871626) and LILRA3 (rs103294) were newly identified as non-HLA susceptibility loci in TAK. Here, we examined how these SNPs contribute to clinical characteristics and vascular damage in TAK. We retrospectively reviewed the medical records of 99 TAK patients enrolled in our previous genome-wide association study, and whose genotypes for IL12B rs6871626, LILRA3 rs103294, and HLA-B*52 were available. Incidence of aortic regurgitation (AR) was significantly associated with the A allele (risk allele) of IL12B rs6871626 (CC 42%, AC 61%, AA 81%; p = 0.0052; odds ratio [OR] 2.45), as well as with the incidence of hypertension (p = 0.049; OR 1.82) and the proportion of patients who underwent aortic valve replacement (p = 0.023; OR 3.64). Regarding vascular damage, there was positive correlation between the Takayasu Arteritis Damage Score and the A allele of IL12B rs6871626 (CC 3.42 ± 2.71, AC 4.06 ± 3.25, AA 6.00 ± 2.81; p = 0.0035; β = 1.35) and between the Vasculitis Damage Index and the A allele (CC 3.47 ± 1.98, AC 4.33 ± 2.40, AA 5.37 ± 2.22; p = 0.0054; β = 0.96). Contrarily, no correlation was found between LILRA3 rs103294 and vascular damage. In the present study, IL12B rs6871626 was associated with vascular damage in TAK, whereas LILRA3 rs103294 was not. Genotyping of IL12B rs6871626 may help to identify patients at risk of disease progression.

DOI： 10.1038/s41598-021-93213-9

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE Publications  

<sec><title>Objectives</title> It is important to clarify the relationship between irreversible organ damage and the quality of life (QOL) by considering the unique factors of patients with systemic lupus erythematosus (SLE). We aimed to clarify their correlation using SLE-specific QOL assessment tools. We also aimed to identify which type of organ damage is adversely correlated with the QOL.

</sec><sec><title>Methods</title> We conducted a questionnaire-based survey of outpatients with SLE at Kyoto University Hospital and evaluated irreversible organ damage using the SLICC/ACR damage index (SDI). LupusPRO and the SLE symptom checklist (SSC) were employed as SLE-specific QOL tools, and the SF-36v2 was used as a conventional QOL tool. Multiple linear regression analyses were performed to examine the correlations between the total SDI score and each QOL score, and between each SDI item/system score and each QOL score.

</sec><sec><title>Results</title> We analyzed the data of 265 patients. The total SDI score was significantly correlated with physical (PCS) and role/social component summary (RCS) of the SF-36v2, health-related QOL (HRQOL) of LupusPRO, and SSC ( p &lt; 0.001). Among the SDI items, atrophy/weakness and osteoporosis with fracture/vertebral collapse were negatively correlated with PCS (β = −0.40, p &lt; 0.001/β = −0.28, p &lt; 0.001), RCS (β = −0.30, p &lt; 0.001/β = −0.35, p &lt; 0.001), and HRQOL (β = −0.34, p &lt; 0.001/β = −0.31, p &lt; 0.001), respectively. Among the SDI systems, musculoskeletal damage had higher negative correlations with PCS (β = −0.51, p &lt; 0.001), RCS (β = −0.29, p &lt; 0.001), and HRQOL (β = −0.40, p &lt; 0.001).

</sec><sec><title>Conclusion</title> We demonstrated the QOL of patients with SLE is negatively correlated with irreversible organ damage. We also revealed musculoskeletal damage is adversely correlated with the health-related QOL, especially the physical and role/social QOL.

</sec>

DOI： 10.1177/09612033211025614

PubMed

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その他リンク： http://journals.sagepub.com/doi/full-xml/10.1177/09612033211025614

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The systemic lupus erythematosus (SLE) symptom checklist (SSC) is a patient-reported outcome measure consisting of 38 queries. We translated SSC into Japanese and attempted to validate its usefulness for evaluating the quality of life (QOL) of SLE patients and identify factors that affect QOL. METHODS: Data from the Medical Outcomes Study Short-form 36 questionnaire (SF-36), Japanese LupusPRO, the Japanese version of the SSC (SSC-J) questionnaire, SLEDAI-2k, and the physician global assessment (PGA) were obtained on the same day from 226 SLE outpatients of the Kyoto Lupus cohort at Kyoto University Hospital. Relationships between the total scores or each item of SSC-J and SF-36, Japanese LupusPRO, SLEDAI-2k, or PGA were analyzed by Spearman's rank test. RESULTS: The total scores of SSC-J correlated with the scores of SF-36 and Japanese LupusPRO. In each item of SSC-J, all 38 items correlated with the physical component summary and mental component summary of SF-36 as well as the Health-Related QOL (HRQOL) scores of Japanese LupusPRO, but not with the non-HRQOL of LupusPRO. SSC-J scores correlated with age, PGA, and corticosteroid doses, but not with SLEDAI-2k. CONCLUSIONS: SSC-J is suitable as a disease-specific QOL assessment tool for SLE.

DOI： 10.1177/09612033211005026

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Genetic studies have revealed many variant loci that are associated with immune-mediated diseases. To elucidate the disease pathogenesis, it is essential to understand the function of these variants, especially under disease-associated conditions. Here, we performed a large-scale immune cell gene-expression analysis, together with whole-genome sequence analysis. Our dataset consists of 28 distinct immune cell subsets from 337 patients diagnosed with 10 categories of immune-mediated diseases and 79 healthy volunteers. Our dataset captured distinctive gene-expression profiles across immune cell types and diseases. Expression quantitative trait loci (eQTL) analysis revealed dynamic variations of eQTL effects in the context of immunological conditions, as well as cell types. These cell-type-specific and context-dependent eQTLs showed significant enrichment in immune disease-associated genetic variants, and they implicated the disease-relevant cell types, genes, and environment. This atlas deepens our understanding of the immunogenetic functions of disease-associated variants under in vivo disease conditions.

DOI： 10.1016/j.cell.2021.03.056

PubMed

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記述言語：日本語   出版者・発行元：日本肺高血圧・肺循環学会・日本小児肺循環研究会  

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記述言語：日本語   出版者・発行元：日本肺高血圧・肺循環学会・日本小児肺循環研究会  

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記述言語：日本語   出版者・発行元：医歯薬出版(株)  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J00060&link_issn=&doc_id=20210531010015&doc_link_id=%2Faa7ayuma%2F2021%2F027709%2F016%2F0735-0741%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa7ayuma%2F2021%2F027709%2F016%2F0735-0741%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

<title>Abstract</title>
<sec>
<title>Objectives</title>
ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- and older-onset patients are still incompletely understood.


</sec>
<sec>
<title>Methods</title>
We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We divided the population according to age at diagnosis: &amp;lt;65 years or ≥65 years. We adjusted associations for the type of AAV and the type of ANCA (anti-MPO, anti-PR3 or negative).


</sec>
<sec>
<title>Results</title>
A total of 1338 patients with AAV were included: 66% had disease onset at &amp;lt;65 years of age [female 50%; mean age 48.4 years (s.d. 12.6)] and 34% had disease onset at ≥65 years [female 54%; mean age 73.6 years (s.d. 6)]. ANCA (MPO) positivity was more frequent in the older group (48% vs 27%; P = 0.001). Younger patients had higher rates of musculoskeletal, cutaneous and ENT manifestations compared with older patients. Systemic, neurologic,cardiovascular involvement and worsening renal function were more frequent in the older-onset group. Damage accrual, measured with the Vasculitis Damage Index (VDI), was significantly higher in older patients, 12% of whom had a 6 month VDI ≥5, compared with 7% of younger patients (P = 0.01). Older age was an independent risk factor for early death within 6 months from diagnosis [hazard ratio 2.06 (95% CI 1.07, 3.97); P = 0.03].


</sec>
<sec>
<title>Conclusion</title>
Within 6 months of diagnosis of AAV, patients &amp;gt;65 years of age display a different pattern of organ involvement and an increased risk of significant damage and mortality compared with younger patients.


</sec>

DOI： 10.1093/rheumatology/keaa215

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We report a case of 68-year-old man with stable polymyositis complicated with primary hepatic lymphoma (PHL) as other iatrogenic immunodeficiency-related lymphoproliferative disorders (OIIA-LPD). Multiple liver masses were diagnosed as diffuse large B-cell lymphoma (DLBCL) by biopsy. The LPD was associated with Epstein-Barr virus (EBV) reactivation, because EBV-DNA was detected in peripheral blood, and EBV antigen was detected in the tumour. He presented with high fever, cytopenia and hyperferritinemia, suggesting hemophagocytosis. Only discontinuation of methotrexate and tacrolimus resulted in a dramatic regression of the liver masses and improvement of fever and cytopenia. We review six cases of OIIA-LPD localised in the liver. All cases were DLBCL; 4/6 cases (67%) were positive for EBV staining, and 2/6 cases (33%) were improved after the discontinuation of immunosuppressants. Screening for EBV in blood and liver tumour is important, when a patient in immunosuppressive status presented with liver masses.

DOI： 10.1080/24725625.2020.1826627

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記述言語：日本語   出版者・発行元：日本脊椎関節炎学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody, a dermatomyositis (DM)-specific antibody, is strongly associated with interstitial lung disease (ILD). Patients with idiopathic inflammatory myopathy (IIM) who are anti-MDA5 antibody positive [anti-MDA5 (+)] often experience chest symptoms during the active disease phase. These symptoms are primarily explained by respiratory failure; nevertheless, cardiac involvement can also be symptomatic. Thus, the aim of this study was to investigate cardiac involvement in anti-MDA5 (+) DM. A total of 63 patients with IIM who underwent electrocardiography (ECG) and ultrasound cardiography (UCG) during the active disease phase from 2016 to 2021 [anti-MDA5 (+) group, n = 21; anti-MDA5-negative (-) group, n = 42] were enrolled in the study, and their clinical charts were retrospectively reviewed. The ECG and UCG findings were compared between the anti-MDA5 (+) and anti-MDA5 (-) groups. All anti-MDA5 (+) patients had DM with ILD. The anti-MDA5 (+) group showed more frequent skin ulcerations and lower levels of leukocytes, muscle enzymes, and electrolytes (Na, K, Cl, and Ca) than the anti-MDA5 (-) group. According to the ECG findings obtained during the active disease phase, the T wave amplitudes were significantly lower for the anti-MDA5 (+) group than for the anti-MDA5 (-) group (I, II, and V4-6 lead; p < 0.01; aVF and V3, p < 0.05). However, the lower amplitudes were restored during the remission phase. Except for the E wave, A wave and Sep e', the UCG results showed no significant differences between the groups. Four patients with anti-MDA5 (+) DM had many leads with lower T wave and cardiac abnormalities (heart failure, diastolic dysfunction, myocarditis) on and after admission. Though anti-MDA5 (+) patients clinically improved after immunosuppressive therapy, some of their ECG findings did not fully recover in remission phase. In conclusion, anti-MDA5 (+) DM appears to show cardiac involvement (electrical activity and function) during the active phase. Further studies are necessary to clarify the actual cardiac condition and mechanism of these findings in patients with anti-MDA5 (+) DM.

DOI： 10.3389/fimmu.2021.765140

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: This study sought to identify the ratio of M1/M2 cells in the infrapatellar fat pads (IFP) and subcutaneous fat tissues (SC) of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. The clinical features of OA and RA patients treated with or without biological disease-modifying anti-rheumatic drugs (bDMARDs) were also assessed. Methods: IFP and SC were collected from patients with OA and RA who are undergoing total knee arthroplasty (TKA). CD14-positive cells were then isolated from these samples. Flow cytometry was used to determine the number of CD14++CD80+ cells and CD14++CD163+ cells. The expression levels of lipid transcription factors, such as sterol regulatory element-binding protein 1 (SREBP1) and liver X receptor alpha (LXRA), and inflammatory cytokines were also evaluated. Results: Twenty OA patients and 22 RA patients were enrolled in this study. Ten of the RA patients (45.4%) received bDAMRDs before TKA. On average, a fivefold increase in the number of CD14-positive cells and lower expression levels of SREBP1C and LXRA were observed in OA IFP relative to OA SC; however, these results were not obtained from the RA samples. The median ratio of CD14++CD80+ cells/CD14++CD163+ cells of OA IFP was 0.87 (0.76-1.09, interquartile range), which is higher to that of OA SC with a lower ratio (p = 0.05835). Conclusions: The quantity and quality of CD14-positive cells differed between IFP and SC in arthropathy patients. To our knowledge, this is the first study to characterize the ratio of M1/M2 cells in the IFP and SC of end-stage OA and RA patients. The increased ratio of CD14++CD80+ cells/CD14++CD163+ cells in the IFP from patients with OA and RA treated with bDMARDs indicated that inflammation was localized in the IFP. As adipose tissue-derived innate immune cells were revealed as one of the targets for regulating inflammation, further analysis of these cells in the IFP may reveal new therapeutic strategies for inflammatory joint diseases.

DOI： 10.3389/fimmu.2021.774177

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Taylor and Francis Ltd.  

DOI： 10.1080/25785826.2021.1874137

Scopus

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Autoantibodies (auto Abs) and inflammatory mediators (IMs) in cerebrospinal fluid (CSF) may be involved in the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE). It is suggested that anti-N-methyl D-aspartate receptor NR2 subunit (NR2) Ab can develop NP manifestation after blood-brain barrier (BBB) abruption. We also reported the association between NPSLE and CSF anti-U1RNP Ab. In the present study, combined effects of CSF anti-NR2 and anti-U1RNP Abs on IMs in patients with NPSLE were examined. METHODS: CSF samples were collected from 69 patients with NPSLE and 13 non-NPSLE controls. CSF anti-NR2 and anti-U1RNP Abs were determined using ELISA. Levels of IL-6, IL-8, and monokine induced by IFN-γ (MIG) in CSF were measured by quantitative multiplex cytokine analysis. RESULTS: CSF IL-6 levels were higher in CSF anti-NR2-positive than in CSF anti-NR2-negative patients (p = 0.003) and non-NPSLE controls (p = 0.015) and were positively correlated with anti-NR2 titer (r = 0.42). CSF IL-8 levels were higher in CSF anti-U1RNP-positive than in CSF anti-U1RNP-negative patients (p = 0.041). CSF MIG levels were more elevated in CSF anti-NR2-positive (p = 0.043) and anti-U1RNP-positive patients (p = 0.029) than in non-NPSLE controls. Additionally, in double positive (DP; both anti-NR2 and U1RNP Ab positive) group, CSF IL-6 and MIG levels were significantly higher than in the double negative (DN; both anti-NR2 and U1RNP Ab negative) group. However, combined effect of both Abs on IM elevation and clinical manifestation was not clear. CONCLUSIONS: CSF anti-NR2 and anti-U1RNP Abs have different effects on the elevation of CSF IM levels in patients with NPSLE. Additional effect of anti-U1RNP Abs on anti-NR2 Ab-mediated NP manifestation, however, was not recognized in our study.

DOI： 10.1177/0961203320954918

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The anti-cyclic citrullinated peptide (CCP) antibody is a diagnostic biomarker of rheumatoid arthritis (RA). However, some non-RA connective tissue disease (CTD) patients also test positive for the anti-CCP antibody and, thus, may ultimately develop RA. We retrospectively investigated whether anti-CCP-positive non-RA CTD patients developed RA and attempted to identify factors that may differentiate RA-overlapping CTD from pure CTD. METHODS: In total, 842 CTD patients with a primary diagnosis that was not RA were selected from our CTD database as of December 2012. Anti-CCP antibody titers were obtained from a retrospective chart review or measured using stored sera. RA was diagnosed according to the 1987 revised American College of Rheumatology classification criteria. Thirty-three anti-CCP-positive non-RA CTD patients were retrospectively followed up for the development of RA. Bone erosions on the hands and feet were assessed by X-ray. Citrullination dependency was evaluated by an in-house ELISA, the HLA-DRB1 allele was typed, and the results obtained were then compared between RA-overlapping and non-RA anti-CCP-positive CTD patients. RESULTS: Two out of 33 anti-CCP-positive CTD patients (6.1%) developed RA during a mean follow-up period of 8.9 years. X-rays were examined in 27 out of the 33 patients, and only one (3.7%) showed bone erosions. The frequency of the HLA-DRB1 shared epitope (SE) and anti-CCP antibody titers were both significantly higher in anti-CCP-positive RA-overlapping CTD patients than in anti-CCP-positive non-RA CTD patients, while no significant differences were observed in citrullination dependency. CONCLUSIONS: Anti-CCP-positive non-RA CTD patients rarely developed RA. HLA-DRB1 SE and anti-CCP antibody titers may facilitate the differentiation of RA-overlapping CTD from anti-CCP-positive non-RA CTD.

DOI： 10.1186/s13075-020-02351-4

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記述言語：日本語   出版者・発行元：日本臨床免疫学会  

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記述言語：日本語   出版者・発行元：(一社)日本臨床免疫学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Biologics have been used to treat refractory Takayasu arteritis (TAK), but their efficacy and safety have not been sufficiently evaluated. METHODS: We extracted clinical information from medical records for TAK patients who were treated with biologics including ustekinumab (UST) at Kyoto University Hospital. We also analysed the patient's genetic backgrounds. RESULTS: Of 163 cases, 12 (7.4%) were treated with infliximab, tocilizumab, or UST (n = 3). Erythrocyte sedimentation rate (ESR), C-reactive protein levels (CRP), and prednisolone (PSL) dose were significantly decreased 12 months after the initiation of biologics. When compared with the 15 patients who were only treated with immunosuppressants (IS group), the change in ESR from baseline was significantly lower in the biologics group than in the IS group (-2 mm/h, p = .005). The proportion of patients with HLA-B*52 and the risk-type alleles of the SNP were similar in both groups. Among the biologics, TCZ showed the highest continuation rate. UST exhibited marginal effects on reducing ESR, CRP levels, and PSL dose. No adverse events were observed in patients with UST for approximately 3 years. CONCLUSIONS: Biological treatments resulted in a reduction in inflammatory markers and PSL dose in refractory TAK patients.

DOI： 10.1080/14397595.2020.1800560

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/rcr2.594

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その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/rcr2.594

記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: We aimed to determine the predicting factors for disappearance of anti-mutated citrullinated vimentin antibody (anti-MCV Ab) in sera from rheumatoid arthritis (RA) patients.Methods: In 2013, 95 RA patients whose Disease Activity Score with erythrocyte sedimentation rate were moderate to severe (DAS28-ESR ≥3.2) at baseline were enrolled. Titers of anti-MCV Ab and anti-cyclic citrullinated peptide (anti-CCP) Ab for 2013 and 2014 were measured. The association of anti-MCV disappearance with disease activity, treatment, interstitial lung disease (ILD), and serum markers of ILD were retrospectively examined. Predicting factors of anti-MCV disappearance were determined by multivariable analysis.Results: While anti-CCP positivity rate did not change during the year, anti-MCV Ab changed from positive to negative in 18 patients (=19.0%). Continuous biological disease-modifying anti-rheumatic drug use, prednisolone dose (≥5.0 mg daily), and low KL-6 level (<191 U/mL) were determined as predicting factors of anti-MCV disappearance by multivariable analysis. In our cohort, anti-MCV Ab disappearance was not linked to clinical and radiological improvement.Conclusion: Different from anti-CCP Ab, anti-MCV Ab in sera from RA patients can disappear in a year. Some predicting factors for such negative seroconversion were found, whereas clinical significance of anti-MCV Ab disappearance was undetermined.

DOI： 10.1080/14397595.2019.1621439

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Rapidly progressive interstitial lung disease (RP-ILD) with poor prognosis often accompanies anti-melanoma differentiation-associated gene 5 (MDA5)-positive DM. Combined immunosuppressive therapy, including glucocorticoids, calcineurin inhibitors and intravenous cyclophosphamide (IVCY) is reportedly effective in DM with RP-ILD, but some patients remain resistant to therapy. We examined the utility of plasma exchange (PE) in such intractable cases and investigated the prognostic factors of the disease. METHODS: Thirty-eight anti-MDA5-positive DM-ILD patients who received the combined immunosuppressive therapy were retrospectively reviewed. Their serum cytokines were evaluated by multiplex assay before treatment. The patients were divided into two groups: those who achieved remission without exacerbation of respiratory dysfunction (n = 25, group A) and those who progressed to hypoxemia during the treatment (n = 13, group B). RESULTS: PE was carried out in eight group B patients, but none of group A. Five of the eight treated with PE survived, while the five untreated patients died (P =0.04). Higher neutrophil lymphocyte ratio, higher serum ferritin, hypoxemia, high-resolution computed tomography (HRCT) score before treatment and increase of Krebs von Lungen-6 (KL-6) in the first 4 weeks of the treatment were the prognostic factors for disease progression. Serum cytokines such as IL-1, IL-6, IL-8, IL-10, IL-12p70, IL-18 and sCD163 levels were higher in group B than group A. CONCLUSION: PE should be an effective adjuvant treatment in anti-MDA5-positive DM with RP-ILD. Assessment of basal laboratory tests or monocyte/macrophage-derived cytokines and the increase of KL-6, HRCT score and hypoxemia may help us to predict intractable cases and to make early treatment decisions regarding PE in anti-MDA5-positive DM.

DOI： 10.1093/rheumatology/keaa123

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Relapses frequently occur in giant cell arteritis (GCA), and long-term glucocorticoid therapy is required. The identification of associated factors with poor treatment outcomes is important to decide the treatment algorithm of GCA. METHODS: We enrolled 139 newly diagnosed GCA patients treated with glucocorticoids between 2007 and 2014 in a retrospective, multi-center registry. Patients were diagnosed with temporal artery biopsy, 1990 American College of Rheumatology classification criteria, or large vessel lesions (LVLs) detected by imaging based on the modified classification criteria. Poor treatment outcomes (non-achievement of clinical remission by week 24 or relapse during 52 weeks) were evaluated. Clinical remission was defined as the absence of clinical signs and symptoms in cranial and large vessel areas, polymyalgia rheumatica (PMR), and elevation of C-reactive protein (CRP) levels. A patient was determined to have a relapse if he/she had either one of the signs and symptoms that newly appeared or worsened after achieving clinical remission. Re-elevation of CRP without clinical manifestations was considered as a relapse if other causes such as infection were excluded and the treatment was intensified. Associated factors with poor treatment outcomes were analyzed by using the Cox proportional hazard model. RESULTS: Cranial lesions, PMR, and LVLs were detected in 77.7%, 41.7%, and 52.5% of the enrolled patients, respectively. Treatment outcomes were evaluated in 119 newly diagnosed patients who were observed for 24 weeks or longer. The mean initial dose of prednisolone was 0.76 mg/kg/day, and 29.4% received any concomitant immunosuppressive drugs at baseline. Overall, 41 (34.5%) of the 119 patients had poor treatment outcomes; 13 did not achieve clinical remission by week 24, and 28 had a relapse after achieving clinical remission. Cumulative rates of the events of poor treatment outcomes in patients with and without LVLs were 47.5% and 17.7%, respectively. A multivariable model showed the presence of LVLs at baseline was significantly associated with poor treatment outcomes (adjusted hazard ratio [HR] 3.54, 95% CI 1.52-8.24, p = 0.003). Cranial lesions and PMR did not increase the risk of poor treatment outcomes. CONCLUSION: The initial treatment intensity in the treatment algorithm of GCA could be determined based upon the presence or absence of LVLs detected by imaging at baseline.

DOI： 10.1186/s13075-020-02171-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective: An anti-carbamylated albumin antibody was detected in rheumatoid arthritis (RA) patients, and its presence was associated with serum myeloperoxidase (MPO) levels, as we reported previously. Since MPO is a key enzyme for carbamylation and is released by neutrophil extracellular traps (NETs), we aimed to demonstrate that NETosis induces carbamylation.Methods: Human neutrophils were isolated from a healthy donor, pre-treated with or without diphenyleneiodonium (DPI, an inhibitor for the generation of reactive oxygen species (ROS)), Cl-amidine (a peptidylarginine deiminase inhibitor), 4-aminobenzoic acid hydrazide (4-ABAH, an MPO inhibitor), or GW311616A (a neutrophil elastase (NE) inhibitor), and incubated for 8 h with or without phorbol 12-myristate 13-acetate (PMA). Proteins in the medium were collected and the carbamylation of albumin was evaluated by Western blotting.Results: The carbamylation of albumin was detected in the culture medium of activated neutrophils. NETosis was observed under the stimulation by PMA. DPI and 4-ABAH inhibited the carbamylation of albumin and NETosis. GW311616A inhibited NETosis, but not carbamylation. Neither carbamylation nor NETosis was inhibited by Cl-amidine.Conclusion: Activated neutrophils may carbamylate ambient albumin, and this is dependent on ROS and MPO, but does not require NETosis.

DOI： 10.1080/14397595.2019.1583819

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Interstitial lung disease (ILD) accompanied by anti-melanoma differentiation-associated gene 5 (anti-MDA-5)-positive dermatomyositis (DM) is often rapidly progressive and associated with poor prognosis. Because there is no established treatment, we undertook this study to prospectively evaluate the efficacy and safety of a combined immunosuppressive regimen for anti-MDA-5-positive DM patients with ILD. METHODS: Adult Japanese patients with new-onset anti-MDA-5-positive DM with ILD (n = 29) were enrolled at multiple study centers from 2014 to 2017. They were treated with a regimen of high-dose glucocorticoids (GCs), tacrolimus, and intravenous cyclophosphamide (IV CYC). Plasmapheresis was used if a patient's condition worsened after the regimen started. The primary end point was 6-month survival, which was compared between this group of patients and a historical control group (n = 15) consisting of anti-MDA-5-positive DM patients with ILD who received step-up treatment (high-dose GC and stepwise addition of immunosuppressant). Secondary end points were 12-month survival rate, adverse events, and changes in laboratory data. RESULTS: The combined immunosuppressive regimen group showed significantly higher 6-month survival rates than the step-up treatment group (89% versus 33%; P < 0.0001). Over a period of 52 weeks, improvements in anti-MDA-5 titers, serum ferritin levels, vital capacity, and chest high-resolution computed tomography scores were observed. The combined immunosuppressive regimen group received IV CYC nearly 20 days earlier with shorter intervals and tended to receive plasmapheresis more often than patients undergoing step-up treatment. Cytomegalovirus reactivation was frequently observed over 52 weeks. CONCLUSION: A combined immunosuppressive regimen is effective for anti-MDA-5-positive DM patients with ILD. Plasmapheresis can be used for additional effect in intractable disease. Patients should be carefully monitored for opportunistic infections during treatment.

DOI： 10.1002/art.41105

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To investigate the long-term efficacy and safety of the IL-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK). METHODS: Patients completing the randomized, double-blind, placebo-controlled period of the TAKT (Takayasu arteritis Treated with Tocilizumab) trial were followed up during open-label extended treatment with weekly s.c. tocilizumab 162 mg for up to 96 weeks or longer, with oral glucocorticoid tapering performed at the investigators' discretion. Endpoints of the extension analysis included steroid-sparing effects of tocilizumab, imaging data, patient-reported outcomes (36-Item Short Form Health Survey) and safety. RESULTS: All 36 patients enrolled in the double-blind period entered the open-label extension; 28 patients received tocilizumab for 96 weeks. The median glucocorticoid dose was 0.223 mg/kg/day at the time of relapse before study entry, 0.131 mg/kg/day (interquartile range 0.099, 0.207) after 48 weeks and 0.105 mg/kg/day (interquartile range 0.039, 0.153) after 96 weeks. Overall, 46.4% of patients reduced their dose to <0.1 mg/kg/day, which was less than half the dose administered at relapse before study entry (mean difference -0.120 mg/kg/day; 95% CI -0.154, -0.087). Imaging evaluations indicated that most patients' disease was improved (17.9%) or stable (67.9%) after 96 weeks compared with baseline. Mean 36-Item Short Form Health Survey physical and mental component summary scores and 7 of 8 domain scores were clinically improved from baseline and maintained over 96 weeks of tocilizumab treatment. No unexpected safety issues were reported. CONCLUSION: These results in patients with Takayasu arteritis provide evidence of a steroid-sparing effect and improvements in well-being during long-term treatment with once-weekly tocilizumab 162 mg, with no new safety concerns. TRIAL REGISTRATION: JAPIC Clinical Trials Information, http://www.clinicaltrials.jp/user/cteSearch_e.jsp, JapicCTI-142616.

DOI： 10.1093/rheumatology/kez630

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To clarify the relationship between dietary habit and disease activity of rheumatoid arthritis (RA). METHODS: This study enrolled RA patients who met the ACR/EULAR 2010 classification criteria from Kyoto University Rheumatoid Arthritis Management Alliance (KURAMA) cohort in 2015. 22-item food frequency questionnaire (FFQ) was taken for the measurement of dietary habit in a single-institution cohort of RA (Kyoto University Rheumatoid Arthritis Management Alliance: KURAMA) in 2015. The disease activities of RA using the Disease Activity Score calculated based on the erythrocyte sedimentation rate (DAS28-ESR), Simplified Disease Activity Index (SDAI), Health Assessment Questionnaire (HAQ), and serum matrix metalloproteinase-3 (MMP-3) level, the use of disease-modifying anti-rheumatic drugs (DMARDs), disease duration, rheumatoid factor, anti-cyclic citrullinated antibody, and body mass index were also examined. All of them were combined and statistically analyzed. RESULTS: 441 RA patients (81% women; mean age 65 years; mean disease duration 15 years) were enrolled from the KURAMA cohort. Average Disease Activity Score-28 using the erythrocyte sedimentation rate (DAS28-ESR) was 2.7. Univariate analysis showed that intake frequency of vegetables had a statistically significant negative correlation with disease activity markers, such as DAS28-ESR (ρ = -0.11, p<0.01), Simplified Disease Activity Index (SDAI) (ρ = -0.16, p<0.001), matrix metalloproteinase-3 (MMP-3) (ρ = -0.21, p<0.0001), and Health Assessment Questionnaire (HAQ) (ρ = -0.13, p<0.01). Factor analysis with varimax rotation was done to simplify the relevance of disease activity to various food items. 22 foods were categorized into five dietary patterns: "seafoods", "vegetables/fruits", "meats/fried foods", "snacks", and "processed foods". The multivariate analysis adjusted for clinically significant confounders showed that "seafoods" had statistically significant negative correlations with DAS28-ESR (β = -0.15, p<0.01), SDAI (β = -0.18, p<0.001), MMP-3 (β = -0.15, p<0.01), and HAQ (β = -0.24, p<0.0001). "Vegetables/fruits" had statistically significant negative correlations with SDAI (β = -0.11 p<0.05), MMP-3 (β = -0.12, p<0.01), and HAQ (β = -0.11, p<0.05). CONCLUSIONS: These results suggest that high intake frequency of vegetables/fruits and/or seafoods might correlate with low disease activity.

DOI： 10.1371/journal.pone.0228852

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/14397595.2019.1703522

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記述言語：日本語   出版者・発行元：日本脊椎関節炎学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Takayasu arteritis (TAK) affects the aorta and its primary branches, mainly in young women. In its advanced stages, it can cause severe complications, such as cerebral infarction, impaired vision, and valvular heart diseases. In the aortic tissue of TAK, there is increased infiltration of cytotoxic lymphocytes, such as natural killer (NK) cells and CD8+T cells, and enhanced expression of accessory molecules, such as major histocompatibility complex (MHC) and MHC class I chain-related gene (MIC) family. Genome-wide association studies on TAK have identified susceptibility genes, such as IL-12p40, MICA, MICB, leukocyte immunoglobulin-like receptor A3 (LILRA3), and LILRB3. Other studies have also shown their involvement in the pathophysiology of TAK. In addition, we reported the importance of NK cells by enhancer enrichment analysis. These results suggest that the gene polymorphisms that potentially upregulate the expression of cytokines and accessory molecules, which contribute to the activation of cytotoxic lymphocytes, are associated with the development of TAK. Based on these results, new molecular targeted therapies look promising.

DOI： 10.1186/s41232-020-00119-6

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記述言語：日本語   出版者・発行元：日本臨床免疫学会  

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記述言語：日本語   出版者・発行元：日本臨床免疫学会  

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記述言語：日本語   出版者・発行元：日本臨床免疫学会  

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記述言語：日本語   出版者・発行元：(株)日本医事新報社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A defect in TCR-proximal signaling is a major characteristic of CD4 T cells in systemic lupus erythematosus; however, it is not fully known how defects in TCR signaling lead to lupus-like systemic autoimmunity characterized by germinal center development and autoantibody production against nuclear Ags. In this study, we show that SKG mice, which develop autoimmune arthritis in a BALB/c background due to defective TCR signaling by a Zap70 mutation, develop lupus-like systemic autoimmune disease in the C57BL/6 (B6) background (B6SKG mice). B6SKG mice showed multiorgan inflammation with immune complex deposition and anti-dsDNA Ab production. Follicular helper T cells (Tfh), which help germinal center formation, were spontaneously expanded in B6SKG mice. Th cells secreting IFN-γ or IL-17 and regulatory T cells were also increased in B6SKG mice compared with wild-type B6 mice, with the regulatory T cell subpopulation losing the expression of CD25. Among the factors related to Tfh differentiation, the number of dendritic cells and the expression levels of the costimulatory molecules CD80, CD86, and ICOSL in dendritic cells but not in B cells were specifically increased in wild-type B6 mice compared with BALB/c mice. The inhibition of these costimulatory molecules suppressed Tfh development and lupus-like autoimmunity. Thus, a defect in TCR-proximal signaling leads to lupus-like systemic autoimmunity under the specific genetic background that facilitates Tfh development.

DOI： 10.4049/jimmunol.1801159

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記述言語：日本語   出版者・発行元：(NPO)日本呼吸器内視鏡学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE Publications Ltd  

DOI： 10.1177/0961203319828818

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DOI： 10.1080/14397595.2018.1546358

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

DOI： 10.1080/24725625.2019.1569798

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記述言語：日本語   出版者・発行元：日本脊椎関節炎学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B*52 is an established susceptibility locus to TAK. To date, there are still only a limited number of reports concerning non-HLA susceptibility loci to TAK. We conducted a genome-wide association study (GWAS) and a follow-up study in a total of 633 TAK cases and 5,928 controls. A total of 510,879 SNPs were genotyped, and 5,875,450 SNPs were imputed together with HLA-B*52. Functional annotation of significant loci, enhancer enrichment, and pathway analyses were conducted. We identified four unreported significant loci, namely rs2322599, rs103294, rs17133698, and rs1713450, in PTK2B, LILRA3/LILRB2, DUSP22, and KLHL33, respectively. Two additional significant loci unreported in non-European GWAS were identified, namely HSPA6/FCGR3A and chr21q.22. We found that a single variant associated with the expression of MICB, a ligand for natural killer (NK) cell receptor, could explain the entire association with the HLA-B region. Rs2322599 is strongly associated with the expression of PTK2B Rs103294 risk allele in LILRA3/LILRB2 is known to be a tagging SNP for the deletion of LILRA3, a soluble receptor of HLA class I molecules. We found a significant epistasis effect between HLA-B*52 and rs103294 (P = 1.2 × 10-3). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells (P = 8.8 × 10-5, enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect between LILRA3 and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK.

DOI： 10.1073/pnas.1808850115

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-018-28405-x

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/14397595.2017.1416739

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

DOI： 10.1080/24725625.2018.1469819

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Tokyo  

DOI： 10.1007/s00535-017-1420-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Suppressor of TCR signaling-2 (STS-2) is one of the RA susceptibility genes identified in genome-wide association studies (GWAS). We tried to verify the involvement of STS-2 on the development of autoimmune arthritis in a mouse model. METHODS: STS-2 knock-out (KO) and wild type (WT) mice were immunized with chicken type II collagen (CII). For CD4+ helper T cell (Th) subset analysis, intracellular cytokines in splenocytes and lymph node cells were stained and analyzed by flow cytometry. Regulatory T cell (Treg) function was analyzed by co-culturing effector CD4+T cells and Tregs collected from non-immunized mice. RESULTS: CII-immunized STS-2 KO mice developed arthritis more frequently than WT mice. Although the T cell activation profile and Th subset in spleen and LNs were similar between STS-2 KO and WT mice, STS-2 KO mice showed increased IL-2-producing CD4+T cells in spleen when compared with WT mice. Accordingly, STS-2 KO CD4+T cells promoted IL-2 production by TCR stimulation. However, STS-2 KO Tregs normally suppressed T cell proliferation. CONCLUSION: We proved that STS-2 is involved in the arthritis development by collagen-induced arthritis. Higher IL-2 production from STS-2 KO T cells is suggested to have a main pathogenic role in arthritis development.

DOI： 10.1080/14397595.2017.1380249

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DOI： 10.3109/14397595.2016.1153443

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1038/s41379-018-0036-4

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その他リンク： http://www.nature.com/articles/s41379-018-0036-4.pdf

記述言語：日本語   出版者・発行元：(一社)日本リウマチ学会  

DOI： 10.1093/rap/rky022

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BioMed Central Ltd.  

DOI： 10.1186/s13075-018-1511-5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0184738

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3899/jrheum.161432

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s13075-017-1408-8

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記述言語：英語  

DOI： 10.1002/art.40108

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Anti-centromere antibody (ACA) is one of the classical anti-nuclear antibody (ANA) staining patterns. However, characteristics of ACA in comparison with the other ANA patterns and clinical features of ACA-positive subjects have not been elucidated. Here, we examined all ANA patterns by indirect immunofluorescence for 859 rheumatoid arthritis (RA) patients. Together with the ANA data of 9,575 healthy volunteers, we compared distributions of the ANA levels. ACA was the only ANA that demonstrated a definite bimodal distribution of levels. ACA showed significantly higher levels than the other ANA staining patterns in both RA and healthy population (p < 0.0001). ACA-positivity was associated with old age and was observed more in females. We further recruited another cohort of 3,353 RA patients and confirmed the findings. ACA was also associated with Raynaud's phenomenon (p = 6.8 × 10-11) in RA. As a conclusion, ACA displays a specific ANA staining pattern with a bimodal distribution, and ACA-positive RA may constitute a distinct subset with specific clinical features.

DOI： 10.1038/s41598-017-07137-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/rheumatology/kex088

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease characterised by skin and systemic fibrosis culminating in organ damage. Previous genetic studies including genome-wide association studies (GWAS) have identified 12 susceptibility loci satisfying genome-wide significance. Transethnic meta-analyses have successfully expanded the list of susceptibility genes and deepened biological insights for other autoimmune diseases. METHODS: We performed transethnic meta-analysis of GWAS in the Japanese and European populations, followed by a two-staged replication study comprising a total of 4436 cases and 14 751 controls. Associations between significant single nuclear polymorphisms (SNPs) and neighbouring genes were evaluated. Enrichment analysis of H3K4Me3, a representative histone mark for active promoter was conducted with an expanded list of SSc susceptibility genes. RESULTS: We identified two significant SNP in two loci, GSDMA and PRDM1, both of which are related to immune functions and associated with other autoimmune diseases (p=1.4×10-10 and 6.6×10-10, respectively). GSDMA also showed a significant association with limited cutaneous SSc. We also replicated the associations of previously reported loci including a non-GWAS locus, TNFAIP3. PRDM1 encodes BLIMP1, a transcription factor regulating T-cell proliferation and plasma cell differentiation. The top SNP in GSDMA was a missense variant and correlated with gene expression of neighbouring genes, and this could explain the association in this locus. We found different human leukocyte antigen (HLA) association patterns between the two populations. Enrichment analysis suggested the importance of CD4-naïve primary T cell. CONCLUSIONS: GSDMA and PRDM1 are associated with SSc. These findings provide enhanced insight into the genetic and biological basis of SSc.

DOI： 10.1136/annrheumdis-2016-210645

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1756-185X.13000

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jaut.2016.11.006

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3109/14397595.2014.948981

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DOI： 10.1155/2017/9312142

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Hindawi Limited  

DOI： 10.1155/2017/9312142

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/14397595.2016.1220353

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japan Society for Clinical Immunology  

DOI： 10.2177/jsci.40.118

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0167141

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/rheumatology/kew233

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.55.6565

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

TAFRO syndrome is a newly defined disease entity which is characterized by thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly. A histological pattern of multiple lymphadenopathy of atypical Castleman's disease (CD) is also an important characteristic. A 48-year-old man was referred to our hospital with fever, asthenia, bilateral pleural effusion, ascites, generalized edema, dyspnea, hypoalbuminemia, severe thrombocytopenia, anemia, renal failure and proteinuria, whereas bacterial culture and serological and PCR tests for various viruses were all negative. A CT scan showed multiple lymphadenopathy and tissue sampling of inguinal lymph nodes showed a compatible histology with plasma cell type CD. A diagnosis of TAFRO syndrome was made. Ten days after hospitalization, sudden cardiac insufficiency and anuria developed. Despite glucocorticoid pulse therapy, tocilizumab and plasmapheresis, clinical and laboratory features did not improve. On the 34(th) hospital day, we started rituximab. His general condition started to improve in several days, and by one month later anasarca had improved drastically. Thrombocytopenia and renal function gradually improved and finally normalized. Cardiac motion also improved. This is the first report of a TAFRO syndrome patient with cardiomyopathy, who was successfully treated with rituximab.

DOI： 10.2177/jsci.39.64

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.55.5553

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0144952

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/acr.22598

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/art.39157

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12891-015-0584-4

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記述言語：英語   出版者・発行元：SAGE Publications Ltd  

DOI： 10.4137/CCRPM.S36748

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記述言語：日本語   出版者・発行元：日本臨床免疫学会  

【背景】Rosai-Dorfman disease（RDD）はリンパ節腫脹を呈する非腫瘍性組織球増殖性疾患であり，骨，皮膚，中枢神経などの臓器病変を認めるとされるが，画像上大動脈病変の報告はごく稀にあるものの，病理組織学的に証明された報告はない．【症例】58歳男性．2008年胸部X線で右胸壁腫瘤を指摘，CTガイド下肺生検では診断がつかず，その後腫瘤は増大し発熱，炎症反応も認めたため胸腔鏡下肺部分切除施行され，組織球浸潤を伴う器質化肺炎とされた．同時に胸部大動脈瘤を指摘され，FDG-PETで集積を認めたため高安動脈炎を疑われ当科紹介された．MRIでは上行～腹部大動脈の壁肥厚および造影効果を認め，虹彩炎，関節炎も伴っていた．前医胸壁病理標本を再検討した結果，S100（+）CD68（+）CD1a（−）組織球の著明な浸潤を認め，emperipolesisが存在したことからRDDと診断した．ステロイド大量投与は効果不十分で，シクロフォスファミド間歇静注療法も無効であり，2年後トシリズマブを開始した．発熱，虹彩炎，関節炎に対しては著効し，大動脈瘤の増大も抑制したが，脳内病変が発症した．クラドリビンと放射線治療の併用により縮小がみられたが，最終的に多発脳梗塞のため死亡した．剖検の結果，硬膜，骨，心外膜などに加え，大動脈へのRDDの浸潤が確認された．【結論】本例が最初の大動脈病変の浸潤を剖検で証明された貴重な症例と考え報告した．

DOI： 10.2177/jsci.38.371a

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記述言語：英語  

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DOI： 10.1002/iid3.17

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/0961203314522337

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3109/14397595.2013.843765

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1177/0961203314523870

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記述言語：英語  

DOI： 10.1111/1756-185X.12309

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3899/jrheum.130270

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/jhg.2013.129

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0085376

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2169/internalmedicine.53.2688

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japan Society for Clinical Immunology  

DOI： 10.2177/jsci.37.454

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japan Society for Clinical Immunology  

DOI： 10.2177/jsci.37.166

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10165-012-0736-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/rheumatology/ket241

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ajhg.2013.05.024

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1346-8138.12184

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0062231

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0059341

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記述言語：日本語   出版者・発行元：The Japan Society for Clinical Immunology  

「ワークショップ選出演題「ワークショップW5-2」抄録は343ページ参照」<br>

DOI： 10.2177/jsci.36.386b

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Multicentric Castleman's disease (MCD) is a rare polyclonal lymphoproliferative disorder that manifests with lymphadenopathy and inflammatory symptoms. In order to clarify the clinical features and actual management of MCD in Japan, we analyzed 21 patients diagnosed with MCD and treated in Kyoto University Hospital between 2005 and 2012. There were 12 men and 9 women. The median age at disease onset was 46 years, and the median follow-up period was 98 months. Common symptoms included splenomegaly (13/20), renal dysfunction (11/21), interstitial pneumonia (7/21), pleural effusion and/or ascites (7/21), and thrombocytopenia (6/21). The results of the anti-human immunodeficiency virus antibody and human herpes virus-8 DNA tests in the blood were available in 13 and 5 cases, respectively, and no patient was positive for either. Among 12 patients treated with tocilizumab, an anti-interleukin-6 receptor antibody, 11 exhibited an improvement in MCD-related symptoms and 3 achieved complete resolution of all these symptoms. In 8 patients treated with tocilizumab for over 1 year, the mean Hb level increased from 7.4 to 12.2 g/dL while the mean serum C-reactive protein level decreased from 13.2 to 0.4 mg/dL. Three patients died during the observation period due to sepsis, secondary leukemia, or pancreatic cancer. The clinical courses of most cases were indolent; however, in some cases with pleural effusion, ascites, renal dysfunction, and/or thrombocytopenia, the disease manifestation was serious. A nationwide survey is required to further clarify the epidemiology, clinical features, and optimal treatment strategies of MCD in Japan.

DOI： 10.3960/jslrt.53.69

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記述言語：日本語   出版者・発行元：The Japan Society for Clinical Immunology  

【背景と目的】<br>  GWASによって自己免疫疾患に関する多数の関連遺伝子が同定されているが，MCTDに関してはHLA以外はこれまで報告がない．抗U1-RNP抗体陽性膠原病はレイノー現象や肺高血圧症を伴いやすいなど共通の特徴を示すため，我々はMCTDを中心とした抗U1-RNP抗体陽性膠原病患者についてGWASを行なった．<br> 【方法】<br>  288人の抗U1-RNP抗体陽性膠原病患者と657人の健常人についてGWASを行なった．タイピングにはIllumina Infinium HumanExome BeadChip Kit（246,006個のSNPを搭載）を用いた．Call rate>0.95，minor allele frequency>0.05，ハーディー・ワインバーグ平衡検定でP値>0.00001を基準としてQuality Control (QC）を行なった．<br> 【結果】<br>  24,525個のSNPと286人の患者，657人の健常人がQC基準を通過した．<br>  その中でHLA-DRA（rs3129878，オッズ比1.87，p=6.32×10⁻¹⁰）およびBLK（rs2618476，オッズ比1.86，p=3.44×10⁻⁷）が有意（p<2.04×10⁻⁶）な関連を示し，STAT4（rs7601754，オッズ比2.03，p=3.11×10⁻⁶）も弱い関連が認められた．<br>  またMCTDの診断基準を満たす例に限ってサブ解析を行なうと，HLA-DRAが最も強い関連を示すとともに，MCTD独自の遺伝子としてCCDC8，SEMA6Dが疾患と関連する可能性が示唆された．<br> 【結論】<br>  抗U1-RNP抗体陽性膠原病に関連する遺伝子と共に，MCTD独自の疾患関連遺伝子の存在が示唆された．<br>

DOI： 10.2177/jsci.36.343b

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その他リンク： http://search.jamas.or.jp/link/ui/2014119058

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/j.1365-2249.2012.04638.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10165-011-0582-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.febslet.2012.01.010

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記述言語：日本語   出版者・発行元：The Japan Society for Clinical Immunology  

Myelin basic protein（MBP）は神経ミエリン鞘を形成する主要なタンパクであるが，関節リウマチ（RA）において，myelin basic proteinに対する自己抗体が高率に認められることを我々は以前報告した（PLoS One 2011; 6: e20457）．ヒト脳由来抽出タンパクを抗原として用いた場合，抗MBP抗体はRAの約65%に認められ，特異度は膠原病患者を対照として83%であり，またその対応抗原は主にMBPタンパク自身ではなく，シトルリン化MBPに対する抗体であることも明らかにした．一方，MBPは神経系に発現するclassic MBPと神経系のみならず血球系にも発現するGolli-MBPのアイソフォームがあり，それぞれにまたいくつかのアイソフォームが存在する．RAで認められる抗MBP抗体の対応抗原がclassic MBPなのかGolli-MBPなのかは不明であったことから，classic MBPおよびGolli-MBPのrecombinantタンパクを作成しin vitroでシトルリン化し，ELISAで抗MBP抗体を検出したところ，その感度，特異度に差は認められなかった．現在Golli-MBPのアミノ酸配列（304アミノ酸）を15種類の25アミノ酸ペプチドでカバーし，それぞれのペプチドをシトルリン化して抗原とし，12人の抗MBP抗体陽性RA患者血清を用いてELISAにてエピトープマッピングを行っている．<br>

DOI： 10.2177/jsci.35.310a

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その他リンク： http://search.jamas.or.jp/link/ui/2012350609

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/ar3810

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0027020

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.4049/jimmunol.1000224

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/ar3546

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/rheumatology/kep375

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/art.24687

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10165-007-0627-2

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記述言語：英語  

DOI： 10.1097/BOR.0b013e3282f01a8c

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10165-006-0559-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10165-006-0560-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/08916930600622884

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記述言語：日本語   出版者・発行元：日本臨床免疫学会  

症例：24歳男性．平成8年に発熱，定型的皮疹，多関節痛，白血球増多，リウマトイド因子・抗核抗体陰性より成人スティル病（ＡＳＤ）と診断され，副腎皮質ステロイドとメトトレキサート（ＭＴＸ）の内服を中心に経過観察されていた．平成16年3月に再燃（発熱，ＣＲＰ上昇）を認めたため，ＭＴＸとシクロスポリンの併用を開始したが無効であった．同年9月よりインフリキシマブ（3mg/kg）の投与を開始したが炎症所見の改善が認められず中止となった．平成17年6月頃から，慢性的な全身倦怠感と炎症所見の持続（ＣＲＰ 5.3mg/dL)を認め，原疾患のコントロールが必要と考えられたため当科入院となった．ステロイド骨粗鬆症に伴う多発性圧迫骨折があり，副腎皮質ステロイド製剤は増量せず（ベタメサゾン 3mg/日）同年7月よりエタネルセプト25mg週2回の投与を開始し，更にメトトレキサートを25mg/週まで増量したが炎症所見の改善は認められなかった．そこで同年10月，エタネルセプトからタクロリムス3mg/日の投与に変更したところ，全身倦怠感の消失と炎症所見の正常化，また血清IL-18の低下傾向を認めた．本症例より，ＴＮＦ多剤阻害療法を含む多剤無効のASDにおいて，タクロリムスの投与も検討すべきと考えられた．

DOI： 10.14906/jscisho.34.0.68.0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1093/intimm/dxh311

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記述言語：日本語   出版者・発行元：日本臨床免疫学会  

【目的】 抗Ku抗体は日本人の強皮症（SSc）+多発性筋炎（PM）の重複症候群に見出される自己抗体として報告された．しかし，米国ではSLEに最も多く検出されると報告され，人種ごとの遺伝的背景の違いによると考察されてきた．そこで我々は抗Ku抗体陽性の自験例について臨床的特徴を検討した．【方法】 2001年から2004年までに当院で診療した膠原病とその疑い例1185例の保存血清についてRNA免疫沈降法を施行し，高分子核酸スメアを沈降した血清をさらに³⁵S‐メチオニン標識HeLa細胞を用いた蛋白免疫沈降法を行って抗Ku抗体を同定した．【結果】 70kDa / 80kDa蛋白へテロ２量体を免疫沈降する抗Ku抗体は6例（0.51％）に陽性であり，SLEとPMの重複例２例，SLE 2例（1例はCK値上昇あり），PM 1例，未分類膠原病（レイノー現象・手指硬化症・クリオグロブリン血症・CK値上昇）1例であった．抗Ku抗体陽性6例中，PMないし筋病変は5例に，SLEないしSLE様症状は4例に，両者の重複は3例に認められた．また，多発関節炎が5例に，レイノー現象が4例に，手指硬化などの強皮症様症状が2例に認められた．【結語】 少数例の解析ではあるが，抗Ku抗体は筋炎重複症候群と関連し，特徴的な臨床像を示す可能性が示唆された．

DOI： 10.14906/jscisho.33.0.36.0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1002/art.20023

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PubMed

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記述言語：日本語   出版者・発行元：日本臨床免疫学会  

DOI： 10.14906/jscisho.27.0.268.0

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その他リンク： http://search.jamas.or.jp/link/ui/2004315400

記述言語：日本語   出版者・発行元：日本臨床免疫学会  

DOI： 10.14906/jscisho.27.0.259.0

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その他リンク： http://search.jamas.or.jp/link/ui/2004315383

記述言語：日本語   出版者・発行元：日本臨床免疫学会  

DOI： 10.14906/jscisho.27.0.274.1

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その他リンク： http://search.jamas.or.jp/link/ui/2004315410

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.2177/jsci.27.427

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